Aspartyl protease inhibitors

ABSTRACT

Disclosed are compounds of the formula I  
                 
 
or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein U, W, R, R 1 , R 2, R   3  and R 4  are as defined in the specification; and pharmaceutical compositions comprising the compounds of formula I. 
 
     Also disclosed is the method of inhibiting aspartyl protease, and in particular, the methods of treating cardiovascular diseases, cognitive and neurodegenerative diseases. Also disclosed are methods of treating cognitive or neurodegenerative diseases using the compounds of formula I in combination with a cholinesterase inhibitor or a muscarinic m 1  agonist or m 2  antagonist.

RELATED APPLICATIONS

This application claims priority to provisional application U.S. Ser.No. 60/690,326, filed on Jun. 14, 2005, herein incorporated byreference.

FIELD OF THE INVENTION

This invention relates to aspartyl protease inhibitors, pharmaceuticalcompositions comprising said compounds, their use in the treatment ofcardiovascular diseases, cognitive and neurodegenerative diseases, andtheir use as inhibitors of the Human Immunodeficiency Virus,plasmepsins, cathepsin D and protozoal enzymes.

BACKGROUND

There are a number of aspartic proteases known to date, including pepsinA and C, renin, BACE, BACE 2, Napsin A, and cathepsin D, which have beenimplicated in pathological conditions. The role of renin-angiotensinsystem (RAS) in regulation of blood pressure and fluid electrolyte hasbeen well established (Oparil, S, et al. N Engl J Med 1974;291:381-401/446-57). The octapeptide Angiotensin-II, a potentvasoconstrictor and stimulator for release of adrenal aldosterone, wasprocessed from the precursor decapeptide Angiotensin-I, which in turn isprocessed from angiotensinogen by the renin enzyme. Angiotensin-II isalso found to play roles in vascular smooth muscle cell growth,inflammation, reactive oxygen species generation and thrombosis andinfluence atherogenesis and vascular damage. Clinically, the benefit ofinterruption of the generation of angiotensin-II through antagonism ofconversion of angiotensin-I has been well known and there are a numberof ACE inhibitor drugs on the market. The blockade of the earlierconversion of angiotensinogen to angiotensin-I, i.e. the inhibition ofrenin enzyme, is expected to have similar but not identical effects.Since renin is an aspartyl protease whose only natural substrate isangiotensinogen, it is believed that there would be less frequentadverse effect for controlling high blood pressure and related symptomsregulated by angiotensin-II through its inhibition.

Another protease, Cathepsin-D, is involved in lysosomal biogenesis andprotein targeting, and may also be involved in antigen processing andpresentation of peptide fragments. It has been linked to numerousdiseases including, Alzheimer's, Disease, connective tissue disease,muscular dystrophy and breast cancer.

Alzheimer's Disease (AD) is a progressive neurodegenerative disease thatis ultimately fatal. Disease progression is associated with gradual lossof cognitive function related to memory, reasoning, orientation andjudgment. Behavioral changes including confusion, depression andaggression also manifest as the disease progresses. The cognitive andbehavioral dysfunction is believed to result from altered neuronalfunction and neuronal loss in the hippocampus and cerebral cortex. Thecurrently available AD treatments are palliative, and while theyameliorate the cognitive and behavioral disorders, they do not preventdisease progression. Therefore there is an unmet medical need for ADtreatments that halt disease progression.

Pathological hallmarks of AD are the deposition of extracellularβ-amyloid (Aβ) plaques and intracellular neurofibrillary tanglescomprised of abnormally phosphorylated protein tau. Individuals with ADexhibit characteristic Aβ deposits, in brain regions known to beimportant for memory and cognition. It is believed that Aβ is thefundamental causative agent of neuronal cell loss and dysfunction whichis associated with cognitive and behavioral decline. Amyloid plaquesconsist predominantly of Aβ peptides comprised of 40-42 amino acidresidues, which are derived from processing of amyloid precursor protein(APP). APP is processed by multiple distinct protease activities. Aβpeptides result from the cleavage of APP by β-secretase at the positioncorresponding to the N-terminus of Aβ, and at the C-terminus byγ-secretase activity. APP is also cleaved by α-secretase activityresulting in the secreted, non-amyloidogenic fragment known as solubleAPP.

An aspartyl protease known as BACE-1 has been identified as theβ-secretase activity responsible for cleavage of APP at the positioncorresponding to the N-terminus of Aβ peptides.

Accumulated biochemical and genetic evidence supports a central role ofAβ in the etiology of AD. For example, Aβ has been shown to be toxic toneuronal cells in vitro and when injected into rodent brains.Furthermore inherited forms of early-onset AD are known in whichwell-defined mutations of APP or the presenilins are present. Thesemutations enhance the production of Aβ and are considered causative ofAD.

Since Aβ peptides are formed as a result of β-secretase activity,inhibition of BACE-1 should inhibit formation of Aβ peptides. Thusinhibition of BACE-1 is a therapeutic approach to the treatment of ADand other cognitive and neurodegenerative diseases caused by Aβ plaquedeposition.

Human immunodeficiency virus (HIV), is the causative agent of acquiredimmune deficiency syndrome (AIDS). It has been clinically demonstratedthat compounds such as indinavir, ritonavir and saquinavir which areinhibitors of the HIV aspartyl protease result in lowering of viralload. As such, the compounds described herein would be expected to beuseful for the treatment of AIDS. Traditionally, a major target forresearchers has been HIV-1 protease, an aspartyl protease related torenin.

In addition, Human T-cell leukemia virus type I (HTLV-I) is a humanretrovirus that has been clinically associated with adult T-cellleukemia and other chronic diseases. Like other retroviruses, HTLV-Irequires an aspartyl protease to process viral precursor proteins, whichproduce mature virions. This makes the protease an attractive target forinhibitor design. (Moore, et al. Purification of HTLV-I Protease andSynthesis of Inhibitors for the treatment of HTLV-I Infection 55^(th)Southeast Regional Meeting of the American Chemical Society, Atlanta,Ga., US Nov. 16-19, 2003 (2003), 1073. CODEN; 69EUCH Conference, AN2004:137641 CAPLUS).

Plasmepsins are essential aspartyl protease enzymes of the malarialparasite. Compounds for the inhibition of aspartyl proteasesplasmepsins, particularly I, II, IV and HAP, are in development for thetreatment of malaria. (Freire, et al. WO 2002074719. Na Byoung-Kuk, etal., Aspartic proteases of Plasmodium vivax are highly conserved in wildisolates, Korean Journal of Parasitology (June 2004), 42(2) 61-6.Journal code: 9435800) Furthermore, compounds used to target aspartylproteases plasmepsins (e.g. I, II, IV and HAP), have been used to killmalarial parasites, thus treating patients thus afflicted.

Compounds that act as aspartyl protease inhibitors are described, forexample, in application U.S. Ser. No. 11/010,772, filed on Dec. 13,2004, herein incorporated by reference.

WO/9304047, herein incorporated by reference, describes compounds havinga quinazolin-2-(thi)one nucleus. The document alleges that the compoundsdescribed therein are inhibitors of HIV reverse transcriptase.

US Publication No. US 2005/0282826 A1, herein incorporated by reference,describes diphenylimidazopyrimidine or -imidazole amines, which are saidto be useful for the therapeutic treatment, prevention or ameliorationof a disease or disorder characterized by elevated β-amyloid deposits orβ-amyloid levels in a patient. Disease states mentioned in thepublication include Alzheimer's disease, mild cognative impairment,Down's syndrome, hereditary cerebral hemorrhage with amyloidosis of theDutch type, cerebral amyloid angiopathy and degenerative dementia.

US Publication No. US 2005/0282825 A1, herein incorporated by reference,describes amino-5,5-diphenylimidazolones, which are said to be usefulfor the therapeutic treatment, prevention or amelioration of a diseaseor disorder characterized by elevated β-amyloid deposits or β-amyloidlevels in a patient. Disease states mentioned in the publication includeAlzheimer's disease, mild cognative impairment, Down's syndrome,hereditary cerebral hemorrhage with amyloidosis of the Dutch type,cerebral amyloid angiopathy and degenerative dementia.

Other publications that disclosed compounds that are useful for treatingAlzherimer's disease include WO 2006/044492, which disclosesspiropiperidine compounds that are said to be inhibitors of β-secretase,and WO 2006/041404, which discloses substituted amino compounds that aresaid to be useful for the treatment or prophylaxix of Aβ relatedpathologies. Both these publications are incorporated by reference.

SUMMARY OF THE INVENTION

The present invention relates to compounds having the structural formulaI

or a stereoisomer, tautomer, or pharmaceutically acceptable salt orsolvate thereof, wherein

W is a bond, —S(O)—, —S(O)₂—, —C(═O)—, —O—, —C(═S)—, —C(═O)—,—C(R⁶)(R⁷)—, —(C(R⁶)(R⁷))—(C(R⁶)(R⁷))—, —N(R⁵)— or —C(═N(R⁵))—;

U is a bond, —S(O)—, —S(O)₂—, —C(O)—, —(C(R⁶)(R⁷))—(C(R⁶)(R⁷))— or—(C(R⁶)(R⁷))—;

R is 1-5 substituents independently selected from the group consistingof H, alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,heterocycloalkylalkyl, arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl,heterocycloalkenylheteroaryl, —NO₂, halo, HO-alkoxyalkyl, —CF₃, —CN,alkyl-CN, —C(O)R³⁰, —C(O)OH, —C(O)OR³⁰, —C(O)NHR³¹, —C(O)NH₂,—C(O)NH₂—C(O)N(alkyl)₂, —C(O)N(alkyl)(aryl), —C(O)N(alkyl)(heteroaryl),—SR³⁰, —S(O)R³¹, —S(O)₂R³¹, —S(O)NH₂, —S(O)NH(alkyl),—S(O)N(alkyl)(alkyl), —S(O)NH(aryl), —S(O)₂NH₂, —S(O)₂NHR³⁰,—S(O)₂NH(heterocycloalkyl), —S(O)₂N(alkyl)₂, —S(O)₂N(alkyl)(aryl),—OCF₃, —OH, —OR³¹, —O-heterocycloalkyl, —O-cycloalkylalkyl,—O-heterocycloalkylalkyl, —NH₂, —NHR³¹, —N(alkyl)₂, —N(arylalkyl)₂,—N(arylalkyl)-(heteroarylalkyl), —NHC(O)R³¹, —NHC(O)NH₂,—NHC(O)NH(alkyl), —NHC(O)N(alkyl)(alkyl), —N(alkyl)C(O)NH(alkyl),—N(alkyl)C(O)N(alkyl)(alkyl), —NHS(O)₂R³¹, —NHS(O)₂NH(alkyl),—NHS(O)₂N(alkyl)(alkyl), —N(alkyl)S(O)₂NH(alkyl) and—N(alkyl)S(O)₂N(alkyl)(alkyl);

R¹ and R² are independently selected from the group consisting ofalkylene, arylalkylene, heteroarylalkylene, cycloalkylalkylene,heterocycloalkylalkylene, arylcycloalkylalkylene,heteroarylcycloalkylalkylene, arylheterocycloalkylalkylene,heteroarylheterocycloalkylalkylene, cycloalkylene, arylcycloalkylene,heteroarylcycloalkylene, heterocycloalkylene, arylheterocycloalkylene,heteroarylheterocycloalkylene, alkenylene, arylalkenylene,cycloalkenylene, arylcycloalkenylene, heteroarylcycloalkenylene,heterocycloalkenylene, arylheterocycloalkenylene,heteroarylheterocycloalkenylene, alkynylene, arylalkynylene, arylene,cycloalkylarylene, heterocycloalkylarylene, cycloalkyenylarylene,cycloalkenylarylene, heterocycloalkenylarylene, heteroarylene,cycloalkylheteroarylene, heterocycloalkylheteroarylene,cycloalkenylheteroarylene and heterocycloalkenylheteroarylene; or

R¹ and R² together are optionally a C₂ to C₆ carbon chain, wherein, one,two or three ring carbons are optionally replaced by —O—, —C(O)—,—C(S)—, —S(O)—, —S(O)₂— or —N(R⁵)—, and R¹ and R² together with thecarbon atoms to which they are attached, form a 5 to 8 membered ring,optionally substituted by R;

R⁵ is independently selected from the group consisting of H, alkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl,arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl,heterocycloalkenylheteroaryl, —OR¹⁵, —CN, —C(O)R⁸, —C(O)OR⁹, —S(O)R¹⁰,—S(O)₂R¹⁰, —C(O)N(R¹¹)(R¹²), —S(O)N(R¹¹)(R¹²), —S(O)₂N(R¹¹)(R¹²), —NO₂,—N═C(R⁸)₂ and —N(R¹¹)(R¹²);

R³ and R⁴ are independently selected from the group consisting of H,alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,heterocycloalkylalkyl, arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl,heterocycloalkenylheteroaryl, halo, —CH₂—O—Si(R⁹)(R¹⁰)(R¹⁹), —SH, —CN,—OR⁹, —C(O)R⁸, —C(O)OR⁹, —C(O)N(R¹¹)(R¹²), —SR¹⁹, —S(O)N(R¹¹)(R¹²),—S(O)₂N(R¹¹)(R¹²), —N(R¹¹)(R¹²), —N(R¹¹)C(O)R⁸, —N(R¹¹)S(O)R¹⁰,—N(R¹¹)S(O)₂R¹⁰, —N(R¹¹)C(O)N(R¹²)(R¹³), —N(R¹¹)C(O)OR⁹ and —C(═NOH)R⁸;

or R³ and R⁴ together with the carbon atoms to which they are attached,form a 3 to 7 membered cycloalkyl group optionally substituted by R¹⁴,wherein, one, two or three ring carbons are optionally replaced by —O—,—C(O)—, —C(S)—, —S—, —S(O)—, —S(O)₂— or —N(R⁵)—; or

or R³, R⁴, D and E together are

wherein D or E is cycloalkenylene, heterocycloalkenylene, cycloalkylene,heterocycloalkylene, arylene or heteroarylene,

M is —O—, —C(O)—, —S—, —CH₂—, —C(S)—, —S(O)—, —S(O)₂— or —N(R⁵)—;

wherein, one to five ring carbons are replaced by —O—, —C(O)—, —S—,—C(S)—, —S(O)—, —S(O)₂— or —N(R⁵)—;

q is 0, 1 or 2;

or R³, R⁴ and D together are

wherein D is cycloalkenylene, heterocycloalkenylene, cycloalkylene,heterocycloalkylene, arylene or heteroarylene,

wherein, one to five ring carbons are replaced by —O—, —C(O)—, —S—,—C(S)—, —S(O)—, —S(O)₂— or —N(R⁵)—;

R¹⁴ is 1-5 substituents independently selected from the group consistingof alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,heterocycloalkylalkyl, arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl,heterocycloalkenylheteroaryl, halo, —CN, —OR¹⁵, —C(O)R¹⁵, —C(O)OR¹⁵,—C(O)N(R¹⁵)(R¹⁶), —SR¹⁵, —S(O)N(R¹⁵)(R¹⁶), —S(O)₂N(R¹⁵)(R¹⁶),—C(═NOR¹⁵)R¹⁶, —P(O)(OR¹⁵)(OR¹⁶), —N(R¹⁵)(R¹⁶), —N(R¹⁵)C(O)R¹⁶,—N(R¹⁵)S(O)R¹⁶, —N(R¹⁵)S(O)₂R¹⁶, —N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷),—N(R¹⁵)S(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷) and —N(R¹⁵)C(O)OR¹⁶;

with the following provisos that R³ and R⁴ cannot be combined to formsaid multicyclic groups

wherein

M is —CH₂—, —S—, —N(R¹⁹)—, or —O—;

D and E are independently arylene or heteroarylene;

and q is 0, 1 or 2 provided that when q is 2, one M must be a carbonatom and when q is 2, M is optionally a double bond;

and provided that when there are at least two heteroatoms present, therecannot be any adjacent oxygen and/or sulfur atoms present in theabove-described ring systems;

R⁶ and R⁷ are independently selected from the group consisting of H,alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,heterocycloalkylalkyl, arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl,heterocycloalkenylheteroaryl, halo, —CH₂—O—Si(R⁹)(R¹⁰)(R¹⁹), —SH, —CN,—OR⁹, —C(O)R⁸, —C(O)OR⁹, —C(O)N(R¹¹)(R¹²), —SR¹⁹, —S(O)N(R¹¹)(R¹²),—S(O)₂N(R¹¹)(R¹²), —N(R¹¹)(R¹²), —N(R¹¹)C(O)R⁸, —N(R¹¹)S(O)R¹⁰,—N(R¹¹)S(O)₂R¹⁰, —N(R¹¹)C(O)N(R¹²)(R¹³), —N(R¹¹)C(O)OR⁹ and —C(═NOH)R⁸;

or R⁶ and R⁷ together with the carbon atoms to which they are attached,form a 3 to 7 membered cycloalkyl group optionally substituted by R¹⁴,wherein, one, two or three ring carbons are optionally replaced by —O—,—C(O)—, —C(S)—, —S—, —S(O)—, —S(O)₂— or —N(R⁵)—;

R⁸ is independently selected from the group consisting of H, alkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl,arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl,heterocycloalkenylheteroaryl, —OR¹⁵, —N(R¹⁵)(R¹⁶), —N(R¹⁵)C(O)R¹⁶,—N(R¹⁵)S(O)R¹⁶, —N(R¹⁵)S(O)₂R¹⁶, —N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷),—N(R¹⁵)S(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷) and —N(R¹⁵)C(O)OR¹⁶;

R⁹ is independently selected from the group consisting of H, alkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl,arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl andheterocycloalkenylheteroaryl;

R¹⁰ is independently selected from the group consisting of H, alkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl,arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl,heterocycloalkenylheteroaryl and —N(R¹⁵)(R¹⁶);

R¹¹, R¹² and R¹³ are independently selected from the group consisting ofH, alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,heterocycloalkylalkyl, arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl,heterocycloalkenylheteroaryl, —C(O)R⁸, —C(O)OR⁹, —S(O)R¹⁰, —S(O)₂R₁₀,—C(O)N(R¹⁵)(R¹⁶), —S(O)N(R¹⁵)(R¹⁶), —S(O)₂N(R¹⁵)(R¹⁶) and —CN;

R¹⁴ is 1-5 substituents independently selected from the group consistingof alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,heterocycloalkylalkyl, arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl,heterocycloalkenylheteroaryl, halo, —CN, —OR¹⁵, —C(O)R¹⁵, —C(O)OR¹⁵,—C(O)N(R¹⁵)(R¹⁶), —SR¹⁵, —S(O)N(R¹⁵)(R¹⁶), —S(O)₂N(R¹⁵)(R¹⁶),—C(═NOR¹⁵)R¹⁶, —P(O)(OR¹⁵)(OR¹⁶), —N(R¹⁵)(R¹⁶), —N(R¹⁵)C(O)R¹⁶,—N(R¹⁵)S(O)R¹⁶, —N(R¹⁵)S(O)₂R¹⁶, —N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷),—N(R¹⁵)S(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷) and —N(R¹⁵)C(O)OR¹⁶;

R¹⁵, R¹⁶ and R¹⁷ are independently selected from the group consisting ofH, alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,heterocycloalkylalkyl, arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl,heterocycloalkenylheteroaryl, R¹⁸-alkyl, R¹⁸-arylalkyl,R¹⁸-heteroarylalkyl, R¹⁸-cycloalkylalkyl, R¹⁸-heterocycloalkylalkyl,R¹⁸-arylcycloalkylalkyl, R¹⁸-heteroarylcycloalkylalkyl,R¹⁸-arylheterocycloalkylalkyl, R¹⁸-heteroarylheterocycloalkylalkyl,R¹⁸-cycloalkyl, R¹⁸-arylcycloalkyl, R¹⁸-heteroarylcycloalkyl,R¹⁸-heterocycloalkyl, R¹⁸-arylheterocycloalkyl,R¹⁸-heteroarylheterocycloalkyl, R¹⁸-alkenyl, R¹⁸-arylalkenyl,R¹⁸-cycloalkenyl, R¹⁸-arylcycloalkenyl, R¹⁸-heteroarylcycloalkenyl,R¹⁸-heterocycloalkenyl, R¹⁸-arylheterocycloalkenyl,R¹⁸-heteroarylheterocycloalkenyl, R¹⁸-alkynyl, R¹⁸-arylalkynyl,R¹⁸-aryl, R¹⁸-cycloalkylaryl, R¹⁸-heterocycloalkylaryl,R¹⁸-cycloalkenylaryl, R¹⁸-heterocycloalkenylaryl, R¹⁸-heteroaryl,R¹⁸-cycloalkylheteroaryl, R¹⁸-heterocycloalkylheteroaryl,R¹⁸-cycloalkenylheteroaryl, and R¹⁸-heterocycloalkenylheteroaryl;

R¹⁵, R¹⁶ and R¹⁷ are

wherein R²³ numbers 0 to 5 substituents, m is 0 to 6 and n is 0 to 5;

R¹⁸ is 1-5 substituents independently selected from the group consistingof alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,heterocycloalkylalkyl, arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl,heterocycloalkenylheteroaryl, —NO₂, halo, HO-alkoxyalkyl, —CF₃, —CN,alkyl-CN, —C(O)R¹⁹, —C(O)OH, —C(O)OR¹⁹, —C(O)NHR²⁰, —C(O)NH₂,—C(O)NH₂—C(O)N(alkyl)₂, —C(O)N(alkyl)(aryl), —C(O)N(alkyl)(heteroaryl),—SR¹⁹, —S(O)₂R²⁰, —S(O)NH₂, —S(O)NH(alkyl), —S(O)N(alkyl)(alkyl),—S(O)NH(aryl), —S(O)₂NH₂, —S(O)₂NHR¹⁹, —S(O)₂NH(heterocycloalkyl),—S(O)₂N(alkyl)₂, —S(O)₂N(alkyl)(aryl), —OCF₃, —OH, —OR²⁰,—O-heterocycloalkyl, —O-cycloalkylalkyl, —O-heterocycloalkylalkyl, —NH₂,—NHR²⁰, —N(alkyl)₂, —N(arylalkyl)₂, —N(arylalkyl)-(heteroarylalkyl),—NHC(O)R²⁰, —NHC(O)NH₂, —NHC(O)NH(alkyl), —NHC(O)N(alkyl)(alkyl),—N(alkyl)C(O)NH(alkyl), —N(alkyl)C(O)N(alkyl)(alkyl), —NHS(O)₂R²⁰,—NHS(O)₂NH(alkyl), —NHS(O)₂N(alkyl)(alkyl), —N(alkyl)S(O)₂NH(alkyl) and—N(alkyl)S(O)₂N(alkyl)(alkyl);

or two R¹⁸ moieties on adjacent carbons are optionally linked togetherto form

R¹⁹ is alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,heterocycloalkylalkyl, arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl, orheterocycloalkenylheteroaryl,

R²⁰ is halo substituted aryl, alkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkylalkyl,heteroarylcycloalkylalkyl, arylheterocycloalkylalkyl,heteroarylheterocycloalkylalkyl, cycloalkyl, arylcycloalkyl,heteroarylcycloalkyl, heterocycloalkyl, arylheterocycloalkyl,heteroarylheterocycloalkyl, alkenyl, arylalkenyl, cycloalkenyl,arylcycloalkenyl, heteroarylcycloalkenyl, heterocycloalkenyl,arylheterocycloalkenyl, heteroarylheterocycloalkenyl, alkynyl,arylalkynyl, aryl, cycloalkylaryl, heterocycloalkylaryl,cycloalkenylaryl, heterocycloalkenylaryl, heteroaryl,cycloalkylheteroaryl, heterocycloalkylheteroaryl,cycloalkenylheteroaryl, heterocycloalkenylheteroaryl,

and wherein

-   -   each of the each of the alkyl, arylalkyl, heteroarylalkyl,        cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkylalkyl,        heteroarylcycloalkylalkyl, arylheterocycloalkylalkyl,        heteroarylheterocycloalkylalkyl, cycloalkyl, arylcycloalkyl,        heteroarylcycloalkyl, heterocycloalkyl, arylheterocycloalkyl,        heteroarylheterocycloalkyl, alkenyl, arylalkenyl, cycloalkenyl,        arylcycloalkenyl, heteroarylcycloalkenyl, heterocycloalkenyl,        arylheterocycloalkenyl, heteroarylheterocycloalkenyl, alkynyl,        arylalkynyl, aryl, cycloalkylaryl, heterocycloalkylaryl,        cycloalkenylaryl, heterocycloalkenylaryl, heteroaryl,        cycloalkylheteroaryl, heterocycloalkylheteroaryl,        cycloalkenylheteroaryl, heterocycloalkenylheteroaryl, in R, R¹,        R², R³, R⁴, R⁵, R⁶, R⁷ R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ are        independently unsubstituted or substituted by 1 to 5 R²¹ groups        independently selected from the group consisting of alkyl,        arylalkyl, heteroarylalkyl, cycloalkylalkyl,        heterocycloalkylalkyl, arylcycloalkylalkyl,        heteroarylcycloalkylalkyl, arylheterocycloalkylalkyl,        heteroarylheterocycloalkylalkyl, cycloalkyl, arylcycloalkyl,        heteroarylcycloalkyl, heterocycloalkyl, arylheterocycloalkyl,        heteroarylheterocycloalkyl, alkenyl, arylalkenyl, cycloalkenyl,        arylcycloalkenyl, heteroarylcycloalkenyl, heterocycloalkenyl,        arylheterocycloalkenyl, heteroarylheterocycloalkenyl, alkynyl,        arylalkynyl, aryl, cycloalkylaryl, heterocycloalkylaryl,        cycloalkenylaryl, heterocycloalkenylaryl, heteroaryl,        cycloalkylheteroaryl, heterocycloalkylheteroaryl,        cycloalkenylheteroaryl, heterocycloalkenylheteroaryl, halo, —CN,        —OR¹⁵, —C(O)R¹⁵, —C(O)OR¹⁵, —C(O)N(R¹⁵)(R¹⁶) —SR¹⁵,        —S(O)N(R¹⁵)(R¹⁶), —CH(R¹⁵)(R¹⁶), —S(O)₂N(R¹⁵)(R¹⁶),        —C(═NOR¹⁵)R¹⁶, —P(O)(OR¹⁵)(OR¹⁶), —N(R¹⁵)(R¹⁶),        -alkyl-N(R¹⁵)(R¹⁶), —N(R¹⁵)C(O)R¹⁶, —CH₂—N(R¹⁵)C(O)R¹⁶,        —CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —CH₂—R¹⁵; —CH₂N(R¹⁵)(R¹⁶),        —N(R¹⁵)S(O)R¹⁶, —N(R¹⁵)S(O)₂R¹⁶, —CH₂—N(R¹⁵)S(O)₂R¹⁶,        —N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷), —N(R¹⁵)S(O)N(R¹⁶)(R¹⁷),        —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷) —CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷),        —N(R¹⁵)C(O)OR¹⁶, —CH₂—N(R¹⁵)C(O)OR¹⁶, —S(O)R¹⁵, —N₃, —NO₂ and        —S(O)₂R¹⁵;    -   and wherein each of the alkyl, arylalkyl, heteroarylalkyl,        cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkylalkyl,        heteroarylcycloalkylalkyl, arylheterocycloalkylalkyl,        heteroarylheterocycloalkylalkyl, cycloalkyl, arylcycloalkyl,        heteroarylcycloalkyl, heterocycloalkyl, arylheterocycloalkyl,        heteroarylheterocycloalkyl, alkenyl, arylalkenyl, cycloalkenyl,        arylcycloalkenyl, heteroarylcycloalkenyl, heterocycloalkenyl,        arylheterocycloalkenyl, heteroarylheterocycloalkenyl, alkynyl,        arylalkynyl, aryl, cycloalkylaryl, heterocycloalkylaryl,        cycloalkenylaryl, heterocycloalkenylaryl, heteroaryl,        cycloalkylheteroaryl, heterocycloalkylheteroaryl,        cycloalkenylheteroaryl, and heterocycloalkenylheteroaryl groups        in R²¹ are independently unsubstituted or substituted by 1 to 5        R²² groups independently selected from the group consisting of        alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,        heterocycloalkylalkyl, arylcycloalkylalkyl,        heteroarylcycloalkylalkyl, arylheterocycloalkylalkyl,        heteroarylheterocycloalkylalkyl, cycloalkyl, arylcycloalkyl,        heteroarylcycloalkyl, heterocycloalkyl, arylheterocycloalkyl,        heteroarylheterocycloalkyl, alkenyl, arylalkenyl, cycloalkenyl,        arylcycloalkenyl, heteroarylcycloalkenyl, heterocycloalkenyl,        arylheterocycloalkenyl, heteroarylheterocycloalkenyl, alkynyl,        arylalkynyl, aryl, cycloalkylaryl, heterocycloalkylaryl,        cycloalkenylaryl, heterocycloalkenylaryl, heteroaryl,        cycloalkylheteroaryl, heterocycloalkylheteroaryl,        cycloalkenylheteroaryl, heterocycloalkenylheteroaryl, halo,        —CF₃, —CN, —OR¹⁵, —C(O)R¹⁵, —C(O)OR¹⁵, -alkyl-C(O)OR¹⁵,        C(O)N(R¹⁵)(R¹⁶), —SR¹⁵, —S(O)N(R¹⁵)(R¹⁶), —S(O)₂N(R¹⁵)(R¹⁶),        —C(═NOR¹⁵)R¹⁶, —P(O)(OR¹⁵)(OR¹⁶), —N(R¹⁵)(R¹⁶),        -alkyl-N(R¹⁵)(R¹⁶), —N(R¹⁵)C(O)R¹⁶, —CH₂—N(R¹⁵)C(O)R¹⁶,        —N(R¹⁵)S(O)R¹⁶, —N(R¹⁵)S(O)₂R¹⁶, —CH₂—N(R¹⁵)S(O)₂R¹⁶,        —N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷), —N(R¹⁵)S(O)N(R¹⁶)(R¹⁷),        —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷),        —N(R¹⁵)C(O)OR¹⁶, —CH₂—N(R¹⁵)C(O)OR¹⁶, —N₃, —NO₂, —S(O)R¹⁵ and        —S(O)₂R¹⁵;

or two R²¹ or two R²² moieties on adjacent carbons are optionally linkedtogether to form

and when R²¹ or R²² are selected from the group consisting of—C(═NOR¹⁵)R¹⁶, —N(R¹⁵)C(O)R¹⁶, —CH₂—N(R¹⁵)C(O)R¹⁶, —N(R¹⁵)S(O)R¹⁶,—N(R¹⁵)S(O)₂R¹⁶, —CH₂—N(R¹⁵)S(O)₂R¹⁶, —N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷),—N(R¹⁵)S(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷),—CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)OR¹⁶ and —CH₂—N(R¹⁵)C(O)OR¹⁶, R¹⁵and R¹⁶ together are optionally a C₂ to C₄ chain wherein, one, two orthree ring carbons are optionally replaced by —C(O)— or —N(H)— and R¹⁵and R¹⁶, together with the atoms to which they are attached, form a 5 to7 membered ring, optionally substituted by R²³;

R²³ is 1 to 5 groups independently selected from the group consisting ofalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,heterocycloalkylalkyl, arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl,heterocycloalkenylheteroaryl, halo, —CN, —R²⁴, —C(O)R²⁴, —C(O)OR²⁴,—C(O)N(R²⁴)(R²⁵), —SR²⁴, —S(O)N(R²⁴)(R²⁵), —S(O)₂N(R²⁴)(R²⁵), —C(═NOR²⁴)R²⁵, —P(O)(OR²⁴)(OR²⁵), —N(R²⁴)(R²⁵), -alkyl-N(R²⁴)(R²⁵),—N(R²⁴)C(O)R²⁵, —CH₂—N(R²⁴)C(O)R²⁵, —N(R²⁴)S(O)R²⁵, —N(R²⁴)S(O)₂R²⁵,—CH₂—N(R²⁴)S(O)₂R²⁵, —N(R²⁴)S(O)₂N(R²⁵)(R²⁶), —N(R²⁴)S(O)N(R²⁵)(R²⁶),—N(R²⁴)C(O)N(R²⁵)(R²⁶), —CH₂—N(R²⁴)C(O)N(R²⁵)(R²⁶), —N(R²⁴)C(O)OR²⁵,—CH₂—N(R²⁴)C(O)OR²⁵, —S(O)R²⁴ and —S(O)₂R²⁴; and wherein each of thealkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,heterocycloalkylalkyl, arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl andheterocycloalkenylheteroaryl groups in R²³ are independentlyunsubstituted or substituted by 1 to 5 R²⁷ groups independently selectedfrom the group consisting of alkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkylalkyl,heteroarylcycloalkylalkyl, arylheterocycloalkylalkyl,heteroarylheterocycloalkylalkyl, cycloalkyl, arylcycloalkyl,heteroarylcycloalkyl, heterocycloalkyl, arylheterocycloalkyl,heteroarylheterocycloalkyl, alkenyl, arylalkenyl, cycloalkenyl,arylcycloalkenyl, heteroarylcycloalkenyl, heterocycloalkenyl,arylheterocycloalkenyl, heteroarylheterocycloalkenyl, alkynyl,arylalkynyl, aryl, cycloalkylaryl, heterocycloalkylaryl,cycloalkenylaryl, heterocycloalkenylaryl, heteroaryl,cycloalkylheteroaryl, heterocycloalkylheteroaryl,cycloalkenylheteroaryl, heterocycloalkenylheteroaryl, halo, —CF₃, —CN,—OR²⁴, —C(O)R²⁴, —C(O)OR²⁴, alkyl-C(O)OR²⁴, C(O)N(R²⁴)(R²⁵), —SR²⁴,—S(O)N(R²⁴)(R²⁵), —S(O)₂N(R²⁴)(R²⁵), —C(═NOR²⁴)R²⁵, —P(O)(OR²⁴)(OR²⁵),—N(R²⁴)(R²⁵), -alkyl-N(R²⁴)(R²⁵), —N(R²⁴)C(O)R²⁵, —CH₂—N(R²⁴)C(O)R²⁵,—N(R²⁴)S(O)R²⁵, —N(R²⁴)S(O)₂R²⁵, —CH₂—N(R²⁴)S(O)₂R²⁵,—N(R²⁴)S(O)₂N(R²⁵)(R^(26), —N(R) ²⁴)S(O)N(R²⁵)(R²⁶),—N(R²⁴)C(O)N(R²⁵)(R²⁶), —CH₂—N(R²⁴)C(O)N(R²⁵)(R²⁶), —N(R²⁴)C(O)OR²⁵,—CH₂—N(R²⁴)C(O)OR²⁵, —S(O)R²⁴ and —S(O)₂R²⁴;

R²⁴, R²⁵ and R²⁶ are independently selected from the group consisting ofH, alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,heterocycloalkylalkyl, arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl,heterocycloalkenylheteroaryl, R²⁷-alkyl, R²⁷-arylalkyl,R²⁷-heteroarylalkyl, R²⁷-cycloalkylalkyl, R²⁷-heterocycloalkylalkyl,R²⁷-arylcycloalkylalkyl, R²⁷-heteroarylcycloalkylalkyl,R²⁷-arylheterocycloalkylalkyl, R²⁷-heteroarylheterocycloalkylalkyl,R²⁷-cycloalkyl, R²⁷-arylcycloalkyl, R²⁷-heteroarylcycloalkyl,R²⁷-heterocycloalkyl, R²⁷-arylheterocycloalkyl,R²⁷-heteroarylheterocycloalkyl, R²⁷-alkenyl, R²⁷-arylalkenyl,R²⁷-cycloalkenyl, R²⁷-arylcycloalkenyl, R²⁷-heteroarylcycloalkenyl,R²⁷-heterocycloalkenyl, R²⁷-arylheterocycloalkenyl,R²⁷-heteroarylheterocycloalkenyl, R²⁷-alkynyl, R²⁷-arylalkynyl,R²⁷-aryl, R²⁷-cycloalkylaryl, R²⁷-heterocycloalkylaryl,R²⁷-cycloalkenylaryl, R²⁷-heterocycloalkenylaryl, R²⁷-heteroaryl,R²⁷-cycloalkylheteroaryl, R²⁷-heterocycloalkylheteroaryl,R²⁷-cycloalkenylheteroaryl and R²⁷-heterocycloalkenylheteroaryl;

R²⁷ is 1-5 substituents independently selected from the group consistingof alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,heterocycloalkylalkyl, arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl,heterocycloalkenylheteroaryl, —NO₂, halo, —CF₃, —CN, alkyl-CN, —C(O)R²⁸,—C(O)OH, —C(O)OR²⁸, —C(O)NHR²⁹, —C(O)N(alkyl)₂, —C(O)N(alkyl)(aryl),—C(O)N(alkyl)(heteroaryl), —SR²⁸, —S(O)₂R²⁹, —S(O)NH₂, —S(O)NH(alkyl),—S(O)N(alkyl)(alkyl), —S(O)NH(aryl), —S(O)₂NH₂, —S(O)₂NHR²⁸,—S(O)₂NH(aryl), —S(O)₂NH(heterocycloalkyl), —S(O)₂N(alkyl)₂,—S(O)₂N(alkyl)(aryl), —OH, —OR²⁹, —O-heterocycloalkyl,—O-cycloalkylalkyl, —O-heterocycloalkylalkyl, —NH₂, —NHR²⁹, —N(alkyl)₂,—N(arylalkyl)₂, —N(arylalkyl)(heteroarylalkyl), —NHC(O)R²⁹, —NHC(O)NH₂,—NHC(O)NH(alkyl), —NHC(O)N(alkyl)(alkyl), —N(alkyl)C(O)NH(alkyl),—N(alkyl)C(O)N(alkyl)(alkyl), —NHS(O)₂R²⁹, —NHS(O)₂NH(alkyl),—NHS(O)₂N(alkyl)(alkyl), —N(alkyl)S(O)₂NH(alkyl) and—N(alkyl)S(O)₂N(alkyl)(alkyl);

R²⁸ is alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,heterocycloalkylalkyl, arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl orheterocycloalkenylheteroaryl;

R²⁹ is alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,heterocycloalkylalkyl, arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl orheterocycloalkenylheteroaryl;

R³⁰ is independently selected from the group consisting of H, alkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl,arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl,heterocycloalkenylheteroaryl, —OR¹⁵, —N(R¹⁵)(R¹⁶), —N(R¹⁵)C(O)R¹⁶,—N(R¹⁵)S(O)R¹⁶, —N(R¹⁵)S(O)₂R¹⁶, —N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷),—N(R¹⁵)S(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷) and —N(R¹⁵)C(O)OR¹⁶;

and

R³¹ is independently selected from the group consisting of H, alkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl,arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl andheterocycloalkenylheteroaryl.

In another aspect, the invention relates to a pharmaceutical compositioncomprising at least one compound of formula I and a pharmaceuticallyacceptable carrier.

In another aspect, the invention comprises the method of inhibitingaspartyl proteases comprising administering at least one compound offormula I to a patient in need of such treatment.

More specifically, the invention comprises: the method of treating acardiovascular disease such as hypertension, renal failure, congestiveheart failure or another disease modulated by renin inhibition; themethod of treating Human Immunodeficiency Virus; the method of treatinga cognitive or neurodegenerative disease such as Alzheimer's Disease;the method of inhibiting plasmepins I and II for treatment of malaria;the method of inhibiting Cathepsin D for the treatment of Alzheimer'sDisease, breast cancer, and ovarian cancer; and the method of inhibitingprotozoal enzymes, for example inhibition of plasmodium falciparnum, forthe treatment of fungal infections. Said method of treatment compriseadministering at least one compound of formula I to a patient in need ofsuch treatment. In particular, the invention comprises the method oftreating Alzheimer's Disease comprising administering at least onecompound of formula I to a patient in need of such treatment.

In another aspect, the invention comprises the method of treatingAlzheimer's Disease comprising administering to a patient in need ofsuch treatment a combination of at least one compound of formula I and acholinesterase inhibitor or a muscarinic m₁ agonist or m₂ antagonist.

In a final aspect, the invention relates to a kit comprising in separatecontainers in a single package pharmaceutical compositions for use incombination, in which one container comprises a compound of formula I ina pharmaceutically acceptable carrier and a second container comprises acholinesterase inhibitor or a muscarinic m₁ agonist or m₂ antagonist ina pharmaceutically acceptable carrier, the combined quantities being aneffective amount to treat a cognitive disease or neurodegenerativedisease such as Alzheimer's Disease.

DETAILED DESCRIPTION

In general, it is understood that divalent groups, for example where—R¹—R²— is -alkylene-O—C(O)—, are to be read left to right.

Preferred compounds of formula I are those compounds of the followingstructures:

Alternatively, another group of preferred compounds of formula I arethose compounds wherein —R¹—R²— is -alkylene-N(R⁵)—C(O)—,-alkylene-C(O)— or -alkylene-O-alkylene-, even more preferably where Rnumbers 1 to 3 and R is alkyl, halo, —C(O)R³⁰ or —S(O)₂R³¹, even furtherpreferably wherein R³⁰ or R³¹ is alkyl.

Another group of preferred compounds of formula I are those compoundswherein

W is —C(O)—;

U is a bond;

—R¹—R²— is -alkylene-O—C(O)—;

R is halo;

R³ is alkyl;

R⁴ is aryl-R²¹;

R²¹ is aryl-R²²;

and

R²² is —CN.

Another group of preferred compounds of formula I are those compoundswherein

W is —C(O)—;

U is a bond;

—R¹—R²— is —CH₂—C(R)₂—O—C(O)—;

R is F;

R³ is —CH₃;

and

R⁴ is

More preferred compounds of the invention are those compounds of formulaI, wherein

W is —C(O)—;

U is a bond;

—R¹—R²— is —CH₂—CH₂—N(R⁵)—C(O)—;

R is —C(O)R³⁰;

R³ is alkyl;

R⁴ is aryl-R²¹;

R²¹ is aryl-R²²;

R²² is —CN;

and

R³⁰ is alkyl.

More preferred compounds of the invention are those compounds of formulaI, wherein

W is —C(O)—;

U is a bond;

—R¹—R²— is —CH₂—CH₂—N(R⁵)—C(O)—;

R is —C(O)R³⁰;

R³is —CH₃;

R⁴ is

and

R³⁰ is —CH₃.

More preferred compounds of the invention are those compounds of formulaI, wherein

W is —C(O)—;

U is a bond;

—R¹—R²— is —CH₂—CH₂—N(R⁵)—C(O)—;

R is —S(O)₂R³¹;

R³ is alkyl;

R⁴ is aryl-R²¹;

R²¹ is aryl-R²²;

R²² is —CN;

and

R³¹ is alkyl.

More preferred compounds of the invention are those compounds of formulaI, wherein

W is —C(O)—;

U is a bond;

—R¹—R²— is CH₂—CH₂—N(R⁵)—C(O)—;

R is —S(O)₂R³¹;

R³ is —CH₃;

R⁴ is

and

R³¹ is —CH₃.

Another group of preferred compounds of formula I are those compoundswherein

W is —C(O)—;

U is a bond;

—R¹—R²— is —CH₂—CH₂—O—C(R)₂—;

R is alkyl;

R³ is alkyl;

R⁴ is aryl-R²¹;

R²¹ is aryl-R²²;

and

R²² is —CN.

Another group of preferred compounds of formula I are those compoundswherein

W is —C(O)—;

U is a bond;

—R¹—R²— is —CH₂—CH₂—O—C(R)₂—;

R is methyl;

R³is —CH₃;

and

R⁴ is

Further preferred compounds of formula I are those compounds of thefollowing structures:

Alternatively, another group of preferred compounds of formula I arethose compounds wherein —R¹—R²— is -alkylene- or -alkylene-C(O)— andwherein R is H.

Another group of preferred compounds of formula I are those compoundswherein

W is —C(O)—;

U is a —C(R⁶)(R⁷)—;

—R¹—R²— is -alkylene-C(O)—;

R is H;

R³ is H;

R⁴ is H;

R⁶ is alkyl;

and

R⁷ is heteroaryl.

Another group of preferred compounds of formula I are those compoundswherein

W is —C(O)—;

U is a —C(R⁶)(R⁷)—;

—R¹—R²— is —CH₂—C(O)—;

R is H;

R³ is H;

R⁴ is H;

R⁶ is —CH₃;

and

R⁷ is

Another group of preferred compounds of formula I are those compoundswherein

W is —C(O)—;

U is a —C(R⁶)(R⁷)—;

—R¹—R²— is -alkylene-;

R is H;

R³ is H;

R⁴ is H;

R⁶ is alkyl;

and

R⁷is heteroaryl.

Another group of preferred compounds of formula I are those compoundswherein

W is —C(O)—;

U is a —C(R⁶)(R⁷)—;

—R¹—R²— is —CH₂—CH₂—CH₂—CH₂—;

R is H;

R³ is H;

R⁴ is H;

R⁶ is —CH₃;

and

R⁷ is

Another group of preferred compounds of formula I are those compoundswherein

W is —C(O)—;

U is a bond;

—R¹—R²— is -alkylene-;

R is H;

R³ is aryl;

and

R⁴ is aryl.

Another group of preferred compounds of formula I are those compoundswherein

W is —C(O)—;

U is a bond;

—R¹—R²— is —CH₂—CH₂—CH₂—;

R is H;

R³is

and

R⁴ is

An even more preferred group of compounds of formua I are those of theformulas:

It is noted that the carbons of formula I may be replaced with 1 to 3silicon atoms so long as all valency requirements are satisfied.

As used above, and throughout the specification, the following terms,unless otherwise indicated, shall be understood to have the followingmeanings:

“Patient” includes both human and animals.

“Mammal” means humans and other mammalian animals.

“Alkyl” means an aliphatic hydrocarbon group which may be straight orbranched and comprising about 1 to about 20 carbon atoms in the chain.Preferred alkyl groups contain about 1 to about 12 carbon atoms in thechain. More preferred alkyl groups contain about 1 to about 6 carbonatoms in the chain. Branched means that one or more lower alkyl groupssuch as methyl, ethyl or propyl, are attached to a linear alkyl chain.“Lower alkyl” means a group having about 1 to about 6 carbon atoms inthe chain which may be straight or branched. Non-limiting examples ofsuitable alkyl groups include methyl, ethyl, n-propyl, isopropyl,n-butyl, t-butyl, n-pentyl, heptyl, nonyl and decyl.

“Alkenyl” means an aliphatic hydrocarbon group containing at least onecarbon-carbon double bond and which may be straight or branched andcomprising about 2 to about 15 carbon atoms in the chain. Preferredalkenyl groups have about 2 to about 12 carbon atoms in the chain; andmore preferably about 2 to about 6 carbon atoms in the chain. Branchedmeans that one or more lower alkyl groups such as methyl, ethyl orpropyl, are attached to a linear alkenyl chain. “Lower alkenyl” meansabout 2 to about 6 carbon atoms in the chain which may be straight orbranched. Non-limiting examples of suitable alkenyl groups includeethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyland decenyl.

“Alkynyl” means an aliphatic hydrocarbon group containing at least onecarbon-carbon triple bond and which may be straight or branched andcomprising about 2 to about 15 carbon atoms in the chain. Preferredalkynyl groups have about 2 to about 12 carbon atoms in the chain; andmore preferably about 2 to about 4 carbon atoms in the chain. Branchedmeans that one or more lower alkyl groups such as methyl, ethyl orpropyl, are attached to a linear alkynyl chain. “Lower alkynyl” meansabout 2 to about 6 carbon atoms in the chain which may be straight orbranched. Non-limiting examples of suitable alkynyl groups includeethynyl, propynyl, 2-butynyl, 3-methylbutynyl, n-pentynyl, and decynyl.

“Aryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 6 to about 14 carbon atoms, preferably about 6 to about10 carbon atoms. The aryl group can be optionally substituted with oneor more substituents (e.g., R¹⁸, R^(21,) R²², etc.) which may be thesame or different, and are as defined herein or two substituents onadjacent carbons can be linked together to form

Non-limiting examples of suitable aryl groups include phenyl andnaphthyl.

“Heteroaryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 5 to about 14 ring atoms, preferably about 5 to about10 ring atoms, in which one to eight of the ring atoms is an elementother than carbon, for example nitrogen, oxygen or sulfur, alone or incombination. Preferred heteroaryls contain about 5 to about 6 ringatoms. The “heteroaryl” can be optionally substituted by one or more R²¹substituents which may be the same or different, and are as definedherein. The prefix aza, oxa or thia before the heteroaryl root namemeans that at least a nitrogen, oxygen or sulfur atom respectively, ispresent as a ring atom. A nitrogen atom of a heteroaryl can beoptionally oxidized to the corresponding N-oxide. Non-limiting examplesof suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl,pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl,furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl,pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl,imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl,indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl,imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl,pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl,1,2,4-triazinyl, benzothiazolyl and the like.

“Cycloalkyl” means a non-aromatic mono- or multicyclic ring systemcomprising about 3 to about 15 carbon atoms, preferably about 5 to about10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7ring atoms. The cycloalkyl can be optionally substituted with one ormore substituents which may be the same or different, and are as definedabove. Non-limiting examples of suitable monocyclic cycloalkyls includecyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.Non-limiting examples of suitable multicyclic cycloalkyls include1-decalin, norbornyl, adamantyl and the like. Further non-limitingexamples of cycloalkyl include the following

“Cycloalkylether” means a non-aromatic ring of 3 to 15 atoms comprisingan oxygen atom and 2 to 14 carbon atoms. Ring carbon atoms can besubstituted, provided that substituents adjacent to the ring oxygen donot include halo or substituents joined to the ring through an oxygen,nitrogen or sulfur atom.

“Cycloalkenyl” means a non-aromatic mono or multicyclic ring systemcomprising about 3 to about 15 carbon atoms, preferably about 5 to about10 carbon atoms which contains at least one carbon-carbon double bond.The cycloalkenyl ring can be optionally substituted with one or more R²¹substituents which may be the same or different, and are as definedabove. Preferred cycloalkenyl rings contain about 5 to about 7 ringatoms. Non-limiting examples of suitable monocyclic cycloalkenylsinclude cyclopentenyl, cyclohexenyl, cycloheptenyl, and the like.Non-limiting example of a suitable multicyclic cycloalkenyl isnorbornylenyl.

“Heterocyclenyl” (or “heterocycloalkenyl”) means a non-aromaticmonocyclic or multicyclic ring system comprising about 3 to about 14ring atoms, preferably about 5 to about 10 ring atoms, in which one ormore of the atoms in the ring system is an element other than carbon,for example nitrogen, oxygen or sulfur atom, alone or in combination,and which contains at least one carbon-carbon double bond orcarbon-nitrogen double bond. There are no adjacent oxygen and/or sulfuratoms present in the ring system. Preferred heterocyclenyl rings containabout 5 to about 6 ring atoms. The prefix aza, oxa or thia before theheterocyclenyl root name means that at least a nitrogen, oxygen orsulfur atom respectively is present as a ring atom. The heterocyclenylcan be optionally substituted by one or more R²¹ substituents which maybe the same or different. The nitrogen or sulfur atom of theheterocyclenyl can be optionally oxidized to the corresponding N-oxide,S-oxide or S,S-dioxide. Non-limiting examples of suitable monocyclicazaheterocyclenyl groups include 1,2,3,4-tetrahydropyridyl,1,2-dihydropyridyl, 1,4-dihydropyridyl, 1,2,3,6-tetrahydropyridyl,1,4,5,6-tetrahydropyrimidyl, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl,2-pyrazolinyl, and the like. Non-limiting examples of suitableoxaheterocyclenyl groups include 3,4-dihydro-2H-pyran, dihydrofuranyl,fluorodihydrofuranyl, and the like. Non-limiting example of a suitablemulticyclic oxaheterocyclenyl group is 7-oxabicyclo[2.2.1]heptenyl.Non-limiting examples of suitable monocyclic thiaheterocyclenyl ringsinclude dihydrothiophenyl, dihydrothiopyranyl, and the like.

“Halo” means fluoro, chloro, bromo, or iodo groups. Preferred arefluoro, chloro or bromo, and more preferred are fluoro and chloro.

“Haloalkyl” means an alkyl as defined above wherein one or more hydrogenatoms on the alkyl is replaced by a halo group defined above.

“Heterocyclyl” (or heterocycloalkyl) means a non-aromatic saturatedmonocyclic or multicyclic ring system comprising about 3 to about 10ring atoms, preferably about 5 to about 14 ring atoms, in which 1-3,preferably 1 or 2 of the atoms in the ring system is an element otherthan carbon, for example nitrogen, oxygen or sulfur, alone or incombination. There are no adjacent oxygen and/or sulfur atoms present inthe ring system. Preferred heterocyclyls contain about 5 to about 6 ringatoms. The prefix aza, oxa or thia before the heterocyclyl root namemeans that at least a nitrogen, oxygen or sulfur atom respectively ispresent as a ring atom. The heterocyclyl can be optionally substitutedby one or more R²¹ substituents which may be the same or different, andare as defined herein. The nitrogen or sulfur atom of the heterocyclylcan be optionally oxidized to the corresponding N-oxide, S-oxide orS,S-dioxide. Non-limiting examples of suitable monocyclic heterocyclylrings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl,thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl,tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and thelike.

“Arylalkyl” means an aryl-alkyl-group in which the aryl and alkyl are aspreviously described. Preferred aralkyls comprise a lower alkyl group.Non-limiting examples of suitable aralkyl groups include benzyl,2-phenethyl and naphthamethyl. The bond to the parent moiety is throughthe alkyl.

“Arylcycloalkyl” means a group derived from a fused aryl and cycloalkylas defined herein. Preferred arylcycloalkyls are those wherein aryl isphenyl and cycloalkyl consists of about 5 to about 6 ring atoms. Thearylcycloalkyl can be optionally substituted by 1-5 R²¹ substituents.Non-limiting examples of suitable arylcycloalkyls include indanyl and1,2,3,4-tetrahydronaphthyl and the like. The bond to the parent moietyis through a non-aromatic carbon atom.

“Arylheterocycloalkyl” means a group derived from a fused aryl andheterocycloalkyl as defined herein. Preferred arylcycloalkyls are thosewherein aryl is phenyl and heterocycloalkyl consists of about 5 to about6 ring atoms. The arylheterocycloalkyl can be optionally substituted by1-5 R²¹ substituents. Non-limiting examples of suitablearylheterocycloalkyls include

The bond to the parent moiety is through a non-aromatic carbon atom.

Similarly, “heteroarylalkyl” “cycloalkylalkyl” and“heterocycloalkylalkyl” mean a heteroaryl-, cycloalkyl- orheterocycloalkyl-alkyl-group in which the heteroaryl, cycloalkyl,heterocycloalkyl and alkyl are as previously described. It is alsounderstood that the terms “arylcycloalkylalkyl”,“heteroarylcycloalkylalkyl”, “arylheterocycloalkylalkyl”,“heteroarylheterocycloalkylalkyl”, “heteroarylcycloalkyl”,“heteroarylheterocycloalkyl”, “arylcycloalkenyl”,“heteroarylcycloalkenyl”, “heterocycloalkenyl”,“arylheterocycloalkenyl”, “heteroarylheterocycloalkenyl”,“cycloalkylaryl”, “heterocycloalkylaryl”, “heterocycloalkenylaryl”,“heterocycloalkylheteroaryl”, “cycloalkenylaryl”,“cycloalkenylheteroaryl” and “heterocycloalkenylheteroaryl” similarlyrepresented by the combination of the groups aryl-, cycloalkyl-, alkyl-,heteroaryl-, heterocycloalkyl-, cycloalkenyl- and heterocycloalkenyl- aspreviously described. Preferred groups contain a lower alkyl group. Thebond to the parent moiety is through the alkyl.

“Acyl” means an H—C(O)—, alkyl-C(O)—, alkenyl-C(O)—, alkynyl-C(O)— orcycloalkyl-C(O)— group in which the various groups are as previouslydescribed. The bond to the parent moiety is through the carbonyl.Preferred acyls contain a lower alkyl. Non-limiting examples of suitableacyl groups include formyl, acetyl, propanoyl, 2-methylpropanoyl,butanoyl and cyclohexanoyl.

“Alkoxy” means an alkyl-O— group in which the alkyl group is aspreviously described. Non-limiting examples of suitable alkoxy groupsinclude methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and heptoxy.The bond to the parent moiety is through the ether oxygen.

“Alkoxyalkyl” means a group derived from an alkoxy and alkyl as definedherein. The bond to the parent moiety is through the alkyl.

“Arylalkenyl” means a group derived from aryl and alkenyl as definedherein. Preferred arylalkenyls are those wherein aryl is phenyl and thealkenyl consists of about 3 to about 6 atoms. The arylalkenyl can beoptionally substituted by one or more R²⁷ substituents. The bond to theparent moiety is through a non-aromatic carbon atom.

“Arylalkynyl” means a group derived from aryl and alkynyl as definedherein. Preferred arylalkynyls are those wherein aryl is phenyl and thealkynyl consists of about 3 to about 6 atoms. The arylalkynyl can beoptionally substituted by one or more R²⁷ substituents. The bond to theparent moiety is through a non-aromatic carbon atom.

The suffix “ene” on alkyl, aryl, hetercycloalkyl, etc. indicates adivalent moiety, e.g., —CH₂CH₂— is ethylene, and

is para-phenylene.

It is understood that multicyclic divalent groups, for example,arylheterocycloalkylene, can be attached to other groups via bonds thatare formed on either ring of said group. For example,

The term “optionally substituted” means optional substitution with thespecified groups, radicals or moieties, in available position orpositions.

Substitution on a cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, orheteroarylalkyl moiety includes substitution on the ring portion and/oron the alkyl portion of the group.

When a variable appears more than once in a group, or a variable appearsmore than once in the structure of formula I, e.g., R⁶ may appear inboth U and W, the variables can be the same or different.

With reference to the number of moieties (e.g., substituents, groups orrings) in a compound, unless otherwise defined, the phrases “one ormore” and “at least one” mean that there can be as many moieties aschemically permitted, and the determination of the maximum number ofsuch moieties is well within the knowledge of those skilled in the art.With respect to the compositions and methods comprising the use of “atleast one compound of formula I,” one to three compounds of formula Ican be administered at the same time, preferably one.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

The wavy line

as a bond generally indicates a mixture of, or either of, the possibleisomers, e.g., containing (R)— and (S)-stereochemistry. For example,

means containing both

Lines drawn into the ring systems, such as, for example:

indicate that the indicated line (bond) may be attached to any of thesubstitutable ring carbon atoms.

As well known in the art, a bond drawn from a particular atom wherein nomoiety is depicted at the terminal end of the bond indicates a methylgroup bound through that bond to the atom, unless stated otherwise. Forexample:

It should also be noted that any heteroatom with unsatisfied valences inthe text, schemes, examples, structural formulae, and any Tables hereinis assumed to have the hydrogen atom or atoms to satisfy the valences.

Those skilled in the art will recognize that certain compounds offormula I are tautomeric, and all such tautomeric forms are contemplatedherein as part of the present invention.

When, R⁸, for example is, —N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷), and R¹⁶ and R¹⁷ forma ring, the moiety formed, is, for example

Prodrugs and solvates of the compounds of the invention are alsocontemplated herein. A discussion of prodrugs is provided in T. Higuchiand V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of theA.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design,(1987) Edward B. Roche, ed., American Pharmaceutical Association andPergamon Press. The term “prodrug” means a compound (e.g, a drugprecursor) that is transformed in vivo to yield a compound of Formula(I) or a pharmaceutically acceptable salt, hydrate or solvate of thecompound. The transformation may occur by various mechanisms (e.g., bymetabolic or chemical processes), such as, for example, throughhydrolysis in blood. A discussion of the use of prodrugs is provided byT. Higuchi and W. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14of the A.C.S. Symposium Series, and in Bioreversible Carriers in DrugDesign, ed. Edward B. Roche, American Pharmaceutical Association andPergamon Press, 1987.

For example, if a compound of Formula (I) or a pharmaceuticallyacceptable salt, hydrate or solvate of the compound contains acarboxylic acid functional group, a prodrug can comprise an ester formedby the replacement of the hydrogen atom of the acid group with a groupsuch as, for example, (C₁-C₈)alkyl, (C₂-C₁₂)alkanoyloxymethyl,1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms,1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms,alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms,1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms,N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N—(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as β-dimethylaminoethyl),carbamoyl-(C₁-C₂)alkyl, N,N-di(C₁-C₂)alkylcarbamoyl-(C1-C2)alkyl andpiperidino-, pyrrolidino- or morpholino(C₂-C₃)alkyl, and the like.

Similarly, if a compound of Formula (I) contains an alcohol functionalgroup, a prodrug can be formed by the replacement of the hydrogen atomof the alcohol group with a group such as, for example,(C₁-C₆)alkanoyloxymethyl, 1-((C₁-C₆)alkanoyloxy)ethyl,1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl, (C₁-C₆)alkoxycarbonyloxymethyl,N—(C₁-C₆)alkoxycarbonylaminomethyl, succinoyl, (C₁-C₆)alkanoyl,α-amino(C₁-C₄)alkanyl, arylacyl and α-aminoacyl, orα-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independentlyselected from the naturally occurring L-amino acids, P(O)(OH)₂,—P(O)(O(C₁-C₆)alkyl)₂ or glycosyl (the radical resulting from theremoval of a hydroxyl group of the hemiacetal form of a carbohydrate),and the like.

If a compound of Formula (I) incorporates an amine functional group, aprodrug can be formed by the replacement of a hydrogen atom in the aminegroup with a group such as, for example, R-carbonyl, RO-carbonyl,NRR′-carbonyl where R and R′ are each independently (C₁-C₁₀)alkyl,(C₃-C₇)cycloalkyl, benzyl, or R-carbonyl is a natural a-aminoacyl ornatural α-aminoacyl, —C(OH)C(O)OY¹ wherein Y¹ is H, (C₁-C₆)alkyl orbenzyl, —C(OY²)Y³ wherein Y² is (C₁-C₄)alkyl and Y³ is (C₁-C₆)alkyl,carboxy(C₁-C₆)alkyl, amino(C₁-C₄)alkyl or mono-N— ordi-N,N—(C₁-C₆)alkylaminoalkyl, —C(Y⁴)Y⁵ wherein Y⁴ is H or methyl and Y⁵is mono-N— or di-N,N—(C₁-C₆)alkylamino morpholino, piperidin-1-yl orpyrrolidin-1-yl, and the like.

“Solvate” means a physical association of a compound of this inventionwith one or more solvent molecules. This physical association involvesvarying degrees of ionic and covalent bonding, including hydrogenbonding. In certain instances the solvate will be capable of isolation,for example when one or more solvent molecules are incorporated in thecrystal lattice of the crystalline solid. “Solvate” encompasses bothsolution-phase and isolatable solvates. Non-limiting examples ofsuitable solvates include ethanolates, methanolates, and the like.“Hydrate” is a solvate wherein the solvent molecule is H₂O.

“Effective amount” or “therapeutically effective amount” is meant todescribe an amount of compound or a composition of the present inventioneffective in inhibiting aspartyl protease and/or inhibiting BACE-1 andthus producing the desired therapeutic effect in a suitable patient.

The compounds of formula I form salts which are also within the scope ofthis invention. Reference to a compound of formula I herein isunderstood to include reference to salts thereof, unless otherwiseindicated. The term “salt(s)”, as employed herein, denotes acidic saltsformed with inorganic and/or organic acids, as well as basic saltsformed with inorganic and/or organic bases. In addition, when a compoundof formula I contains both a basic moiety, such as, but not limited to apyridine or imidazole, and an acidic moiety, such as, but not limited toa carboxylic acid, zwitterions (“inner salts”) may be formed and areincluded within the term “salt(s)” as used herein. Pharmaceuticallyacceptable (i.e., non-toxic, physiologically acceptable) salts arepreferred, although other salts are also useful. Salts of the compoundsof the formula I may be formed, for example, by reacting a compound offormula I with an amount of acid or base, such as an equivalent amount,in a medium such as one in which the salt precipitates or in an aqueousmedium followed by lyophilization. Acids (and bases) which are generallyconsidered suitable for the formation of pharmaceutically useful saltsfrom basic (or acidic) pharmaceutical compounds are discussed, forexample, by S. Berge et al, Journal of Pharmaceutical Sciences (1977)66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33201-217; Anderson et al, The Practice of Medicinal Chemistry (1996),Academic Press, New York; in The Orange Book (Food & DrugAdministration, Washington, D.C. on their website); and P. HeinrichStahl, Camille G. Wermuth (Eds.), Handbook of Pharmaceutical Salts:Properties, Selection, and Use, (2002) Int'l. Union of Pure and AppliedChemistry, pp. 330-331. These disclosures are incorporated herein byreference thereto.

Exemplary acid addition salts include acetates, adipates, alginates,ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates,borates, butyrates, citrates, camphorates, camphorsulfonates,cyclopentanepropionates, digluconates, dodecylsulfates,ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates,hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides,hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates,methanesulfonates, methyl sulfates, 2-naphthalenesulfonates,nicotinates, nitrates, oxalates, pamoates, pectinates, persulfates,3-phenylpropionates, phosphates, picrates, pivalates, propionates,salicylates, succinates, bisulfates, sulfates, sulfonates (such as thosementioned herein), tartarates, thiocyanates, toluenesulfonates (alsoknown as tosylates,) undecanoates, and the like.

Exemplary basic salts include ammonium salts, alkali metal salts such assodium, lithium, and potassium salts, alkaline earth metal salts such ascalcium and magnesium salts, aluminum salts, zinc salts, salts withorganic bases (for example, organic amines) such as benzathines,diethylamine, dicyclohexylamines, hydrabamines (formed withN,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamines,N-methyl-D-glucamides, t-butyl amines, piperazine,phenylcyclohexylamine, choline, tromethamine, and salts with amino acidssuch as arginine, lysine and the like. Basic nitrogen-containing groupsmay be quarternized with agents such as lower alkyl halides (e.g.methyl, ethyl, propyl, and butyl chlorides, bromides and iodides),dialkyl sulfates (e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates),long chain halides (e.g. decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides), aralkyl halides (e.g. benzyl and phenethylbromides), and others.

All such acid salts and base salts are intended to be pharmaceuticallyacceptable salts within the scope of the invention and all acid and basesalts are considered equivalent to the free forms of the correspondingcompounds for purposes of the invention.

All stereoisomers (for example, geometric isomers, optical isomers andthe like) of the present compounds (including those of the salts,solvates and prodrugs of the compounds as well as the salts and solvatesof the prodrugs), such as those which may exist due to asymmetriccarbons on various substituents, including enantiomeric forms (which mayexist even in the absence of asymmetric carbons), rotameric forms,atropisomers, and diastereomeric forms, are contemplated within thescope of this invention. Individual stereoisomers of the compounds ofthe invention may, for example, be substantially free of other isomers,or may be admixed, for example, as racemates or with all other, or otherselected, stereoisomers. The chiral centers of the present invention canhave the S or R configuration as defined by the IUPAC 1974Recommendations. The use of the terms “salt”, “solvate”, “prodrug” andthe like, is intended to equally apply to the salt, solvate and prodrugof enantiomers, stereoisomers, rotamers, tautomers, racemates orprodrugs of the inventive compounds.

Polymorphic forms of the compounds of formula I, and of the salts,solvates and prodrugs of the compounds of formula I, are intended to beincluded in the present invention

Compounds of formula I can be made using procedures known in the art.The following reaction schemes show typical procedures, but thoseskilled in the art will recognize that other procedures can also besuitable.

In Scheme 1, an iminohydanotoin I can be converted into thecorresponding cyclic carbamate II via treatment with triphosgene orbis(N-hydroxylsuccinate)carbonate.

In Scheme 2, a cyclic urea IV can be generated by treatment ofiminohydantoin III with triphosgene orbis(N-hydroxylsuccinate)carbonate.

In Scheme 3, Iminohydantoin V is converted to a urea VI using methodsimilar to that described in scheme 1 and 2.

In Scheme 4, iminohydantoin VII is refluxed in acetone dimethylacetalwith catalytic amount of TsOH to give compound VIII after workup andpurification.

The following methods are examples used to generate these representativecompounds:

Method A, Step 1

To a solution of aminoester A1 (914 mg, 3.66 mmol) in anhydrous CH₃CN(10 ml) at 0° C. was added ethoxycarbonylthioisocyanate (828 mg, 6.31mmol) and the mixture was stirred at rt for 16 hours before it wasconcentrated and the residue purified by column chromatography to giveproduct A2 (1.46 g, 100%; obs. mass 403).

Method A, Step 2

A mixture of A2 (326 mg, 0.857 mmol), glycine methylester (165 mg, 1.31mmol), EDCl (250 mg, 1.30 mmol), and NEt₃ (0.60 ml, 4.3 mmol) in DMF (5ml) was stirred at RT for 3 days. The mixture was diluted with CH₂Cl₂(50 ml) and extracted with saturated NaHCO₃ (60 ml) and water (80 ml).The organic layer was dried over MgSO₄, concentrated, and purified bycolumn chromatography (gradient 0-1.5% MeOH/CH₂Cl₂) to give the productA3 (332 mg, 96%; obs. Mass 404).

Method A, Step 3

A mixture of A3 (322 mg, 0.823 mmol) and 1N NaOH (5 ml) in MeOH (10 ml)was stirred at rt for 1.5 hours. The mixture was partitioned betweenEtOAc (50 ml) and 5N HCl (10 ml). The aqueous layer was extracted withEtOAc (50 ml) and the combined organic portions were washed with water(100 ml), dried over MgSO₄, and concentrated to give the product A4 (166mg, 52%; obs. Mass, 390).

Method A, Step 4

A mixture A4 (44 mg, 0.11 mmol) and oxalyl chloride (15 μl, 0.18 mmol)in CH₂Cl₂ (5 ml) was stirred at RT for 1 hour. Aminomethylcyclopropane(100 μl, 1.15 mmol) was added and the mixture was stirred at RT for 16hours. The mixture was diluted with CH₂Cl₂ (50 ml) and extracted withsaturated Na₂CO₃ (50 ml) and saturated NH₄Cl (50 ml). The organic layerwas dried over MgSO₄, concentrated, and purified by preparative TLC (3%MeOH/CH₂Cl₂) to give the product A5 (13 mg, 25%; obs. Mass 443).

Method A, Step 5

A mixture of A5 (13 mg, 0.028 mmol) and bromotrimethylsilane (20 μl,0.15 mmol) in NMP (0.6 ml) was heated to 120° C. in a microwave reactorfor 30 minutes. The mixture was partitioned between CH₂Cl₂ (50 ml) andsaturated NaHCO₃ (50 ml). The organic layer was washed with water (60ml), dried over MgSO₄, concentrated, and purified by preparative silicagel plates (6% MeOH/CH₂Cl₂) to give A6 (4.1 mg, 48%). ¹H—NMR (CDCl₃)δ7.86 (m, 1H), 7.81 (m, 1H), 7.49 (m, 1H), 7.46 (m, 1H), 7.28 (m, 1H),4.16 (d, 1H, J=17 Hz), 4.01 (d, 1H, J=17 Hz), 3.49 (m, 1H), 3.02 (m,1H), 1.98 (s, 3H). Obs. Mass, 300, 322.

Method B, Step 1.

A mixture of A2 (55 mg, 0.14 mmol), 4-amino-1-butanol (21 mg, 0.23mmol), EDCl (41 mg, 0.21 mmol), and NEt₃ (57 μl, 0.41 mmol) in DMF (3ml) was stirred at rt for 3 days and then heated to 70° C. for 5 hours.The mixture was diluted with CH₂Cl₂ (40 ml) and extracted with saturatedNaHCO₃ (50 ml). The organic layer was washed with water (100 ml), driedover MgSO₄, concentrated, and purified by preparative silica gel plates(3% MeOH/CH₂Cl₂) to give the product B1 (56 mg, 97%; obs. Mass 404).

Method B, Step 2.

A mixture of B1 (28 mg, 0.071 mmol) and bromotrimethylsilane (46 μl,0.35 mmol) in NMP (2 ml) was heated to 120° C. in a microwave reactorfor 30 minutes. The mixture was partitioned between CH₂Cl₂ (50 ml) andsaturated NaHCO₃ (50 ml) and the organic layer was washed with water(2×100 ml), dried over MgSO₄, concentrated. The residue was purified bypreparative silica gel plates (10% MeOH/CH₂Cl₂) to give the product (2mg, 9%). ¹H—NMR (CDCl₃) δ7.81 (m, 2H), 7.42 (m,₁ H), 7.35 (m, 2H),3.0-3.4 (m, 3H), 2.80 (m, 1 H), 1.5-1.9 (m, 9H); obs. Mass; 314)

Method C, Step 1,

A mixture of N—Cbz-1,3-diaminopropane, hydrochloride (C1, 1.22 g) in DMF(15 mL) with triethylamine (1.4 mL) and then N,N-di(Boc)-S-methylurea(C2, 1.46 g) was stirred rt for 72 h. The reaction mixture wasconcentrated in vacuo to give a colorless residue which was purifiedusing silica gel plates and elute with hexane:EtOAc C3 (1.65 g).

Method C, Step 2,

Trifluoroacetic acid (80 mL) was added to compound C3 (1.65 g) in CH₂Cl₂(10 mL) and the resulting mixture was stirred at RT for 3 h before itwas concentrated to give compound C4 as a colorless oil (1.73 g).

Method C, Step 3,

A mixture of C4 (1.65 g), benzil (C5, 0.78 g) and triethylamine (1.96mL) in absolute EtOH (25 mL) was refluxed for 20 h before the reactionmixture was concentrated in vacuo. The residue was partitioned betweenCH₂Cl₂/1N HCl and the organic layer was dried (MgSO₄) and concentratedin vacuo to give a yellow oil (2.40 g) which was purified on silica gelplates eluted with CH₂Cl₂:MeOH 19:1 to give compound C6 (1.38 g).

Method C, Step 4,

A mixture of compound C6, di-tert-butyl-dicarbonate (0.75 g), andtriethylamine (0.60 mL) was stirred at rt for 72 h before the reactionis quenched with ammonia in MeOH, concentrated in vacuo. The residue waspartitioned between CH₂Cl₂/1N HCl and the organic layer was dried(MgSO₄) and concentrated in vacuo to give a white foam (1.57 g) whichwas purified on silica gel plates eluted with CH₂Cl₂:MeOH/98:2 to givecompound C7 as a white residue (0.98 g).

Method C, Step 5:

Compound C7(1.85 g) in absolute EtOH (350 mL) in the presence ofPd(OH)₂/C (10%, 0.75 g) was hydrogenated at rt for 28 h before the solidwas filtered and the solution concentrated in vacuo to give a whitesolid (1.09 g) which was purified on silica gel plates eluted withCH₂Cl₂:MeOH/19:1 to give compound C8 as a white solid (obs. Mass 292).

Human Catheosin D FRET Assay

The substrate used below has been described (Y. Yasuda et al., J.Biochem., 125, 1137 (1999)). Substrate and enzyme are commerciallyavailable.

The assay can be run in a 30 μl final volume using a 384 well Nunc blackplate. 8 concentrations of compound can be pre-incubated with enzyme for30 mins at 37° C. followed by addition of substrate with continuedincubation at 37° C. for 45 mins. The rate of increase in fluorescenceis linear for over 1 h and is measured at the end of the incubationperiod using a Molecular Devices FLEX station plate reader. Kis areinterpolated from the IC₅₀s using a Km value of 4 μM and the substrateconcentration of 2.5 μM.

Reagents

-   Na-Acetate pH 5-   1% Brij-35 from 10% stock (Calbiochem)-   DMSO-   Purified (>95%) human liver Cathepsin D (Athens Research &    Technology Cat #16-12-030104)-   Peptide substrate(Km=4uM)    Mca-Gly-Lys-Pro-Ile-Leu-Phe-Phe-Arg-Leu-Lys(Dnp)-D-Arg-NH₂ Bachem    Cat #M-2455-   Pepstatin is used as a control inhibitor (Ki˜0.5 nM) and is    available from Sigma.-   Nunc 384 well black plates    Final Assay Buffer Conditions-   100 mM Na Acetate pH 5.0-   0.02% Brij-35-   1% DMSO

Compound can be diluted to 3× final concentration in assay buffercontaining 3% DMSO. 10 μl of compound will be added to 10 μl of 2.25 nMenzyme (3×) diluted in assay buffer without DMSO, mixed briefly, spun,and can be incubated at 37° C. for 30 mins. 3× substrate (7.5 μM) isprepared in 1× assay buffer without DMSO. 10 μl of substrate will beadded to each well mixed and spun briefly to initiate the reaction.Assay plates can be incubated at 37 C for 45 mins and read on 384compatible fluorescence plate reader using a 328 nm Ex and 393 nm Em.

BACE-1 Cloning, Protein Expression and Purification

A predicted soluble form of human BACE1 (sBACE1, corresponding to aminoacids 1-454) can be generated from the full length BACE1 cDNA (fulllength human BACE1 cDNA in pCDNA4/mycHisA construct; University ofToronto) by PCR using the advantage-GC cDNA PCR kit (Clontech, PaloAlto, Calif.). A HindIII/Pmel fragment from pCDNA4-sBACE1myc/His can beblunt ended using Klenow and subcloned into the Stu I site ofpFASTBACI(A) (Invitrogen). A sBACE1mycHis recombinant bacmid can begenerated by transposition in DH10Bac cells(GIBCO/BRL). Subsequently,the sBACE1mycHis bacmid construct can be transfected into sf9 cellsusing CellFectin (Invitrogen, San Diego, Calif.) in order to generaterecombinant baculovirus. Sf9 cells are grown in SF 900-II medium(Invitrogen) supplemented with 3% heat inactivated FBS and 0.5×penicillin/streptomycin solution (Invitrogen). Five milliliters of hightiter plaque purified sBACEmyc/His virus is used to infect 1 L oflogarithmically growing sf9 cells for 72 hours. Intact cells arepelleted by centrifugation at 3000×g for 15 minutes. The supernatant,containing secreted sBACE1, is collected and diluted 50% v/v with 100 mMHEPES, pH 8.0. The diluted medium is loaded onto a Q-sepharose column.The Q-sepharose column is washed with Buffer A (20 mM HEPES, pH 8.0, 50mM NaCl).

Proteins, can be eluted from the Q-sepharose column with Buffer B (20 mMHEPES, pH 8.0, 500 mM NaCl). The protein peaks from the Q-sepharosecolumn are pooled and loaded onto a Ni-NTA agarose column. The Ni-NTAcolumn can be then washed with Buffer C (20 mM HEPES, pH 8.0, 500 mMNaCl). Bound proteins are then eluted with Buffer D (Buffer C+250 mMimidazole). Peak protein fractions as determined by the Bradford Assay(Biorad, Calif.) are concentrated using a Centricon 30 concentrator(Millipore). sBACE1 purity is estimated to be ˜90% as assessed bySDS-PAGE and Commassie Blue staining. N-terminal sequencing indicatesthat greater than 90% of the purified sBACE1 contained the prodomain;hence this protein is referred to as sproBACE1.

Peptide Hydrolysis Assay

The inhibitor, 25 nM EuK-biotin labeled APPsw substrate(EuK-KTEEISEVNLDAEFRHDKC-biotin; CIS-Bio International, France), 5 μMunlabeled APPsw peptide (KTEEISEVNLDAEFRHDK; American Peptide Company,Sunnyvale, Calif.), 7 nM sproBACE1, 20 mM PIPES pH 5.0, 0.1% Brij-35(protein grade, Calbiochem, San Diego, Calif.), and 10% glycerol arepreincubated for 30 min at 30° C. Reactions are initiated by addition ofsubstrate in a 5 μl aliquot resulting in a total volume of 25 μl. After3 hr at 30° C. reactions are terminated by addition of an equal volumeof 2× stop buffer containing 50 mM Tris-HCl pH 8.0, 0.5 M KF, 0.001%Brij-35, 20 μg/ml SA-XL665 (cross-linked allophycocyanin protein coupledto streptavidin; CIS-Bio International, France) (0.5 μg/well). Platesare shaken briefly and spun at 1200×g for 10 seconds to pellet allliquid to the bottom of the plate before the incubation. HTRFmeasurements are made on a Packard Discovery® HTRF plate reader using337 nm laser light to excite the sample followed by a 50 μs delay andsimultaneous measurements of both 620 nm and 665 nm emissions for 400μs.

IC₅₀ determinations for inhibitors, (I), are determined by measuring thepercent change of the relative fluorescence at 665 nm divided by therelative fluorescence at 620 nm, (665/620 ratio), in the presence ofvarying concentrations of I and a fixed concentration of enzyme andsubstrate. Nonlinear regression analysis of this data can be performedusing GraphPad Prism 3.0 software selecting four parameter logisticequation, that allows for a variable slope.Y=Bottom+(Top-Bottom)/(1+10ˆ((LogEC50-−X)*Hill Slope)); X is thelogarithm of concentration of I, Y is the percent change in ratio and Ystarts at bottom and goes to top with a sigmoid shape.

Human Mature Renin Enzyme Assay

Human Renin can be cloned from a human kidney cDNA library andC-terminally epitope-tagged with the V5-6His sequence into pCDNA3.1.pCNDA3.1-Renin-V5-6His is stably expressed in HEK293 cells and purifiedto >80% using standard Ni-Affinity chromatography. The prodomain of therecombinant human renin-V5-6His can be removed by limited proteolysisusing immobilized TPCK-trypsin to give mature-human renin. Reninenzymatic activity can be monitored using a commercially availablefluorescence resonance energy transfer (FRET) peptide substrate, RS-1(Molecular Probes, Eugene, Oreg.) in 50 mM Tris-HCl pH 8.0, 100 mM NaCl,0.1% Brij-35 and 5% DMSO buffer for 40 mins at 30° Celsius in thepresence or absence of different concentrations of test compounds.Mature human Renin is present at approximately 200 nM. Inhibitoryactivity is defined as the percent decrease in renin inducedfluorescence at the end of the 40 min incubation compared to vehiclecontrols and samples lacking enzyme.

In the aspect of the invention relating to a combination of at least onecompound of formula I with at least one cholinesterase inhibitor,acetyl- and/or butyrylcholinesterase inhibitors can be used. Examples ofcholinesterase inhibitors are tacrine, donepezil, rivastigmine,galantamine, pyridostigmine and neostigmine, with tacrine, donepezil,rivastigmine and galantamine being preferred. Preferably, thesecombinations are directed to the treatment of Alzheimer's Disease.

In one aspect of the invention, a combination of at least one compoundof formula I with at least one muscarinic ml agonist or m₂ antagonistcan be used. Examples of m₁ agonists are known in the art. Examples ofm₂ antagonists are also known in the art; in particular, m₂ antagonistsare disclosed in U.S. Pat. Nos. 5,883,096; 6,037,352; 5,889,006;6,043,255; 5,952,349; 5,935,958; 6,066,636; 5,977,138; 6,294,554;6,043,255; and 6,458,812; and in WO 03/031412, all of which areincorporated herein by reference.

In other aspects of the invention relating to a combination of at leastone compound of formula I and at least one other agent, for example abeta secretase inhibitor; a gamma secretase inhibitor; an HMG-CoAreductase inhibitor such as atorvastatin, lovastatin, simvastatin,pravastatin, fluvastatin and rosuvastatin; non-steroidalanti-inflammatory agents such as, but not necessarily limited toibuprofen, relafen or naproxen; N-methyl-D-aspartate receptorantagonists such as memantine; anti-amyloid antibodies includinghumanized monoclonal antibodies; vitamin E; nicotinic acetylcholinereceptor agonists; CB1 receptor inverse agonists or CB1 receptorantagonists; antibiotics such as doxycycline; growth hormonesecretagogues; histamine H3 antagonists; AMPA agonists; PDE4 inhibitors;GABA_(A) inverse agonists; inhibitors of amyloid aggregation; glycogensynthase kinase beta inhibitors; promoters of alpha secretase activity.Preferably, these combinations are directed to the treatment ofAlzheimer's Disease.

For preparing pharmaceutical compositions from the compounds describedby this invention, inert, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, dispersible granules, capsules, cachets and suppositories. Thepowders and tablets may be comprised of from about 5 to about 95 percentactive ingredient. Suitable solid carriers are known in the art, e.g.magnesium carbonate, magnesium stearate, talc, sugar or lactose.Tablets, powders, cachets and capsules can be used as solid dosage formssuitable for oral administration. Examples of pharmaceuticallyacceptable carriers and methods of manufacture for various compositionsmay be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences,18th Edition, (1990), Mack Publishing Co., Easton, Pa.

Liquid form preparations include solutions, suspensions and emulsions.As an example may be mentioned water or water-propylene glycol solutionsfor parenteral injection or addition of sweeteners and opacifiers fororal solutions, suspensions and emulsions. Liquid form preparations mayalso include solutions for intranasal administration.

Aerosol preparations suitable for inhalation may include solutions andsolids in powder form, which may be in combination with apharmaceutically acceptable carrier, such as an inert compressed gas,e.g. nitrogen.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally.The transdermal compositions can take the form of creams, lotions,aerosols and/or emulsions and can be included in a transdermal patch ofthe matrix or reservoir type as are conventional in the art for thispurpose.

Preferably the compound is administered orally.

Preferably, the pharmaceutical preparation is in a unit dosage form. Insuch form, the preparation is subdivided into suitably sized unit dosescontaining appropriate quantities of the active component, e.g., aneffective amount to achieve the desired purpose.

The quantity of active compound in a unit dose of preparation may bevaried or adjusted from about 1 mg to about 100 mg, preferably fromabout 1 mg to about 50 mg, more preferably from about 1 mg to about 25mg, according to the particular application.

The actual dosage employed may be varied depending upon the requirementsof the patient and the severity of the condition being treated.Determination of the proper dosage regimen for a particular situation iswithin the skill of the art. For convenience, the total daily dosage maybe divided and administered in portions during the day as required.

The amount and frequency of administration of the compounds of theinvention and/or the pharmaceutically acceptable salts thereof will beregulated according to the judgment of the attending clinicianconsidering such factors as age, condition and size of the patient aswell as severity of the symptoms being treated. A typical recommendeddaily dosage regimen for oral administration can range from about 1mg/day to about 300 mg/day, preferably 1 mg/day to 50 mg/day, in two tofour divided doses.

When a compound of formula I is used in combination with acholinesterase inhibitor to treat cognitive disorders, these two activecomponents may be co-administered simultaneously or sequentially, or asingle pharmaceutical composition comprising a compound of formula I anda cholinesterase inhibitor in a pharmaceutically acceptable carrier canbe administered. The components of the combination can be administeredindividually or together in any conventional oral or parenteral dosageform such as capsule, tablet, powder, cachet, suspension, solution,suppository, nasal spray, etc. The dosage of the cholinesteraseinhibitor can be determined from published material, and may range from0.001 to 100 mg/kg body weight.

When separate pharmaceutical compositions of a compound of formula I anda cholinesterase inhibitor are to be administered, they can be providedin a kit comprising in a single package, one container comprising acompound of formula I in a pharmaceutically acceptable carrier, and aseparate container comprising a cholinesterase inhibitor in apharmaceutically acceptable carrier, with the compound of formula I andthe cholinesterase inhibitor being present in amounts such that thecombination is therapeutically effective. A kit is advantageous foradministering a combination when, for example, the components must beadministered at different time intervals or when they are in differentdosage forms.

While the present invention has been described in conjunction with thespecific embodiments set forth above, many alternatives, modificationsand variations thereof will be apparent to those of ordinary skill inthe art. All such alternatives, modifications and variations areintended to fall within the spirit and scope of the present invention.

1. A compound having the structural formula

or a stereoisomer, tautomer, or pharmaceutically acceptable salt orsolvate thereof, wherein W is a bond, —S(O)—, —S(O)₂—, —C(═O)—, —O—,—C(═S)—, —C(═O)—, —C(R⁶)(R⁷)—, —(C(R⁶)(R⁷))—(C(R⁶)(R⁷))—, —N(R⁵)— or—C(═N(R⁵))—; U is a bond, —S(O)—, —S(O)₂—, —C(O)—,—(C(R⁶)(R⁷))—(C(R⁶)(R⁷))— or —(C(R⁶)(R⁷))—; R is 1-5 substituentsindependently selected from the group consisting of H, alkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl,arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl,heterocycloalkenylheteroaryl, —NO₂, halo, HO-alkoxyalkyl, —CF₃, —CN,alkyl-CN, —C(O)R³⁰, —C(O)OH, —C(O)OR³⁰, —C(O)NHR³¹, —C(O)NH₂,—C(O)NH₂—C(O)N(alkyl)₂, —C(O)N(alkyl)(aryl), —C(O)N(alkyl)(heteroaryl),—SR³⁰, —S(O)R³¹, —S(O)₂R³¹, —S(O)NH₂, —S(O)NH(alkyl),—S(O)N(alkyl)(alkyl), —S(O)NH(aryl), —S(O)₂NH₂, —S(O)₂NHR³⁰,—S(O)₂NH(heterocycloalkyl), —S(O)₂N(alkyl)₂, —S(O)₂N(alkyl)(aryl),—OCF₃, —OH, —OR³¹, —O-heterocycloalkyl, —O-cycloalkylalkyl,—O-heterocycloalkylalkyl, —NH₂, —NHR³¹, —N(alkyl)₂, —N(arylalkyl)₂,—N(arylalkyl)-(heteroarylalkyl), —NHC(O)R³¹, —NHC(O)NH₂,—NHC(O)NH(alkyl), —NHC(O)N(alkyl)(alkyl), —N(alkyl)C(O)NH(alkyl),—N(alkyl)C(O)N(alkyl)(alkyl), —NHS(O)₂R³¹, —NHS(O)₂NH(alkyl),—NHS(O)₂N(alkyl)(alkyl), —N(alkyl)S(O)₂NH(alkyl) and—N(alkyl)S(O)₂N(alkyl)(alkyl); R¹ and R² are independently selected fromthe group consisting of alkylene, arylalkylene, heteroarylalkylene,cycloalkylalkylene, heterocycloalkylalkylene, arylcycloalkylalkylene,heteroarylcycloalkylalkylene, arylheterocycloalkylalkylene,heteroarylheterocycloalkylalkylene, cycloalkylene, arylcycloalkylene,heteroarylcycloalkylene, heterocycloalkylene, arylheterocycloalkylene,heteroarylheterocycloalkylene, alkenylene, arylalkenylene,cycloalkenylene, arylcycloalkenylene, heteroarylcycloalkenylene,heterocycloalkenylene, arylheterocycloalkenylene,heteroarylheterocycloalkenylene, alkynylene, arylalkynylene, arylene,cycloalkylarylene, heterocycloalkylarylene, cycloalkyenylarylene,cycloalkenylarylene, heterocycloalkenylarylene, heteroarylene,cycloalkylheteroarylene, heterocycloalkylheteroarylene,cycloalkenylheteroarylene and heterocycloalkenylheteroarylene; or R¹ andR² together are optionally a C₂ to C₆ carbon chain, wherein, one, two orthree ring carbons are optionally replaced by —O—, —C(O)—, —C(S)—,—S(O)—, —S(O)₂— or —N(R⁵)—, and R¹ and R² together with the carbon atomsto which they are attached, form a 5 to 8 membered ring, optionallysubstituted by R; R⁵ is independently selected from the group consistingof H, alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,heterocycloalkylalkyl, arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl,heterocycloalkenylheteroaryl, —OR¹⁵, —CN, —C(O)R⁸, —C(O)OR⁹, —S(O)R¹⁰,—S(O)₂R¹⁰, —C(O)N(R¹¹)(R¹²), —S(O)N(R¹¹)(R¹²), —S(O)₂N(R¹¹)(R¹²), —NO₂,—N═C(R⁸)₂ and —N(R¹¹)(R¹²); R³ and R⁴ are independently selected fromthe group consisting of H, alkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkylalkyl,heteroarylcycloalkylalkyl, arylheterocycloalkylalkyl,heteroarylheterocycloalkylalkyl, cycloalkyl, arylcycloalkyl,heteroarylcycloalkyl, heterocycloalkyl, arylheterocycloalkyl,heteroarylheterocycloalkyl, alkenyl, arylalkenyl, cycloalkenyl,arylcycloalkenyl, heteroarylcycloalkenyl, heterocycloalkenyl,arylheterocycloalkenyl, heteroarylheterocycloalkenyl, alkynyl,arylalkynyl, aryl, cycloalkylaryl, heterocycloalkylaryl,cycloalkenylaryl, heterocycloalkenylaryl, heteroaryl,cycloalkylheteroaryl, heterocycloalkylheteroaryl,cycloalkenylheteroaryl, heterocycloalkenylheteroaryl, halo,—CH₂—O—Si(R⁹)(R¹⁰)(R¹⁹), —SH, —CN, —OR⁹, —C(O)R⁸, —C(O)OR⁹,—C(O)N(R¹¹)(R¹²), —SR¹⁹, —S(O)N(R¹¹)(R¹²), —S(O)₂N(R¹¹)(R¹²),—N(R¹¹)(R¹²), —N(R¹¹)C(O)R⁸, —N(R¹¹)S(O)R¹⁰, —N(R¹¹)S(O)₂R¹⁰,—N(R¹¹)C(O)N(R¹²)(R¹³), —N(R¹¹)C(O)OR⁹ and —C(═NOH)R⁸; or R³ andR⁴together with the carbon atoms to which they are attached, form a 3 to7 membered cycloalkyl group optionally substituted by R¹⁴, wherein, one,two or three ring carbons are optionally replaced by —O—, —C(O)—,—C(S)—, —S—, —S(O)—, —S(O)₂— or —N(R⁵)—; or or R³, R⁴, D and E togetherare

wherein D or E is cycloalkenylene, heterocycloalkenylene, cycloalkylene,heterocycloalkylene, arylene or heteroarylene, M is —O—, —C(O)—, —S—,—CH₂—, —C(S)—, —S(O)—, —S(O)₂— or —N(R⁵)—; wherein, one to five ringcarbons are replaced by —O—, —C(O)—, —S—, —C(S)—, —S(O)—, —S(O)₂— or—N(R⁵)—; q is 0, 1 or 2; or R³, R⁴ and D together are

wherein D is cycloalkenylene, heterocycloalkenylene, cycloalkylene,heterocycloalkylene, arylene or heteroarylene, wherein, one to five ringcarbons are replaced by —O—, —C(O)—, —S—, —C(S)—, —S(O)—, —S(O)₂— or—N(R⁵)—; R¹⁴ is 1-5 substituents independently selected from the groupconsisting of alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,heterocycloalkylalkyl, arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl,heterocycloalkenylheteroaryl, halo, —CN, —OR¹⁵, —C(O)R¹⁵, —C(O)OR¹⁵,—C(O)N(R¹⁵)(R¹⁶), —SR¹⁵, —S(O)N(R¹⁵)(R¹⁶), —S(O)₂N(R¹⁵)(R¹⁶),—C(═NOR¹⁵)R¹⁶, —P(O)(OR¹⁵)(OR¹⁶), —N(R¹⁵)(R¹⁶), —N(R¹⁵)C(O)R¹⁶,—N(R¹⁵)S(O)R¹⁶, —N(R¹⁵)S(O)₂R¹⁶, —N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷),—N(R¹⁵)S(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷) and —N(R¹⁵)C(O)OR¹⁶; withthe following provisos that R³ and R⁴ cannot be combined to form saidmulticyclic groups

wherein M is —CH₂—, —S—, —N(R¹⁹)—, or —O—; D and E are independentlyarylene or heteroarylene; and q is 0, 1 or 2 provided that when q is 2,one M must be a carbon atom and when q is 2, M is optionally a doublebond; and provided that when there are at least two heteroatoms present,there cannot be any adjacent oxygen and/or sulfur atoms present in theabove-described ring systems; R⁶ and R⁷ are independently selected fromthe group consisting of H, alkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkylalkyl,heteroarylcycloalkylalkyl, arylheterocycloalkylalkyl,heteroarylheterocycloalkylalkyl, cycloalkyl, arylcycloalkyl,heteroarylcycloalkyl, heterocycloalkyl, arylheterocycloalkyl,heteroarylheterocycloalkyl, alkenyl, arylalkenyl, cycloalkenyl,arylcycloalkenyl, heteroarylcycloalkenyl, heterocycloalkenyl,arylheterocycloalkenyl, heteroarylheterocycloalkenyl, alkynyl,arylalkynyl, aryl, cycloalkylaryl, heterocycloalkylaryl,cycloalkenylaryl, heterocycloalkenylaryl, heteroaryl,cycloalkylheteroaryl, heterocycloalkylheteroaryl,cycloalkenylheteroaryl, heterocycloalkenylheteroaryl, halo,—CH₂—O—Si(R⁹)(R¹⁰)(R¹⁹), —SH, —CN, —OR⁹, —C(O)R⁸, —C(O)OR⁹,—C(O)N(R¹¹)(R¹²), —SR¹⁹, —S(O)N(R¹¹)(R¹²), —S(O)₂N(R¹¹)(R¹²),—N(R¹¹)(R¹²), —N(R¹¹)C(O)R⁸, —N(R¹¹)S(O)R¹⁰, —N(R¹¹)S(O)₂R¹⁰,—N(R¹¹)C(O)N(R¹²)(R¹³), —N(R¹¹)C(O)OR⁹ and —C(═NOH)R⁸; or R⁶ and R⁷together with the carbon atoms to which they are attached, form a 3 to 7membered cycloalkyl group optionally substituted by R¹⁴, wherein, one,two or three ring carbons are optionally replaced by —O—, —C(O)—,—C(S)—, —S—, —S(O)—, —S(O)₂— or —N(R⁵); R⁸ is independently selectedfrom the group consisting of H, alkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkylalkyl,heteroarylcycloalkylalkyl, arylheterocycloalkylalkyl,heteroarylheterocycloalkylalkyl, cycloalkyl, arylcycloalkyl,heteroarylcycloalkyl, heterocycloalkyl, arylheterocycloalkyl,heteroarylheterocycloalkyl, alkenyl, arylalkenyl, cycloalkenyl,arylcycloalkenyl, heteroarylcycloalkenyl, heterocycloalkenyl,arylheterocycloalkenyl, heteroarylheterocycloalkenyl, alkynyl,arylalkynyl, aryl, cycloalkylaryl, heterocycloalkylaryl,cycloalkenylaryl, heterocycloalkenylaryl, heteroaryl,cycloalkylheteroaryl, heterocycloalkylheteroaryl,cycloalkenylheteroaryl, heterocycloalkenylheteroaryl, —OR¹⁵,—N(R¹⁵)(R¹⁶), —N(R¹⁵)C(O)R¹⁶, —N(R¹⁵)S(O)R¹⁶, —N(R¹⁵)S(O)₂R¹⁶,—N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷), —N(R¹⁵)S(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷)and —N(R¹⁵)C(O)OR¹⁶; R⁹ is independently selected from the groupconsisting of H, alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,heterocycloalkylalkyl, arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl andheterocycloalkenylheteroaryl; R¹⁰ is independently selected from thegroup consisting of H, alkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkylalkyl,heteroarylcycloalkylalkyl, arylheterocycloalkylalkyl,heteroarylheterocycloalkylalkyl, cycloalkyl, arylcycloalkyl,heteroarylcycloalkyl, heterocycloalkyl, arylheterocycloalkyl,heteroarylheterocycloalkyl, alkenyl, arylalkenyl, cycloalkenyl,arylcycloalkenyl, heteroarylcycloalkenyl, heterocycloalkenyl,arylheterocycloalkenyl, heteroarylheterocycloalkenyl, alkynyl,arylalkynyl, aryl, cycloalkylaryl, heterocycloalkylaryl,cycloalkenylaryl, heterocycloalkenylaryl, heteroaryl,cycloalkylheteroaryl, heterocycloalkylheteroaryl,cycloalkenylheteroaryl, heterocycloalkenylheteroaryl and —N(R¹⁵)(R¹⁶);R¹¹, R¹² and R¹³ are independently selected from the group consisting ofH, alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,heterocycloalkylalkyl, arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl,heterocycloalkenylheteroaryl, —C(O)R⁸, —C(O)OR⁹, —S(O)R¹⁰, —S(O)₂R¹⁰,—C(O)N(R¹⁵)(R¹⁶), —S(O)N(R¹⁵)(R¹⁶), —S(O)₂N(R¹⁵)(R¹⁶) and —CN; R¹⁴ is1-5 substituents independently selected from the group consisting ofalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,heterocycloalkylalkyl, arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl,heterocycloalkenylheteroaryl, halo, —CN, —OR¹⁵, —C(O)R¹⁵, —C(O)OR¹⁵,—C(O)N(R¹⁵)(R¹⁶), —SR¹⁵, —S(O)N(R¹⁵)(R¹⁶), —S(O)₂N(R¹⁵)(R¹⁶),—C(═NOR¹⁵)R¹⁶, —P(O)(OR¹⁵)(OR¹⁶), —N(R¹⁵)(R¹⁶), —N(R¹⁵)C(O)R¹⁶,—N(R¹⁵)S(O)R¹⁶, —N(R¹⁵)S(O)₂R¹⁶, —N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷),—N(R¹⁵)S(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷) and —N(R¹⁵)C(O)OR¹⁶; R¹⁵,R¹⁶ and R¹⁷ are independently selected from the group consisting of H,alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,heterocycloalkylalkyl, arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl,heterocycloalkenylheteroaryl, R¹⁸-alkyl, R¹⁸-arylalkyl,R¹⁸-heteroarylalkyl, R¹⁸-cycloalkylalkyl, R¹⁸-heterocycloalkylalkyl,R¹⁸-arylcycloalkylalkyl, R¹⁸-heteroarylcycloalkylalkyl,R¹⁸-arylheterocycloalkylalkyl, R¹⁸-heteroarylheterocycloalkylalkyl,R¹⁸-cycloalkyl, R¹⁸-arylcycloalkyl, R¹⁸-heteroarylcycloalkyl,R¹⁸-heterocycloalkyl, R¹⁸-arylheterocycloalkyl,R¹⁸-heteroarylheterocycloalkyl, R¹⁸-alkenyl, R¹⁸-arylalkenyl,R¹⁸-cycloalkenyl, R¹⁸-arylcycloalkenyl, R¹⁸-heteroarylcycloalkenyl,R¹⁸-heterocycloalkenyl, R¹⁸-arylheterocycloalkenyl,R¹⁸-heteroarylheterocycloalkenyl, R¹⁸-alkynyl, R¹⁸-arylalkynyl,R¹⁸-aryl, R¹⁸-cycloalkylaryl, R¹⁸-heterocycloalkylaryl,R¹⁸-cycloalkenylaryl, R¹⁸-heterocycloalkenylaryl, R¹⁸-heteroaryl,R¹⁸-cycloalkylheteroaryl, R¹⁸-heterocycloalkylheteroaryl,R¹⁸-cycloalkenylheteroaryl, and R¹⁸-heterocycloalkenylheteroaryl; R¹⁵,R¹⁶ and R¹⁷are

wherein R²³ numbers 0 to 5 substituents, m is 0 to 6 and n is 0 to 5;R¹⁸ is 1-5 substituents independently selected from the group consistingof alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,heterocycloalkylalkyl, arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl,heterocycloalkenylheteroaryl, —NO₂, halo, HO-alkoxyalkyl, —CF₃, —CN,alkyl-CN, —C(O)R¹⁹, —C(O)OH, —C(O)OR¹⁹, —C(O)NHR²⁰, —C(O)NH₂,—C(O)NH₂—C(O)N(alkyl)₂, —C(O)N(alkyl)(aryl), —C(O)N(alkyl)(heteroaryl),—SR¹⁹, —S(O)₂R²⁰, —S(O)NH₂, —S(O)NH(alkyl), —S(O)N(alkyl)(alkyl),—S(O)NH(aryl), —S(O)₂NH₂, —S(O)₂NHR¹⁹, —S(O)₂NH(heterocycloalkyl),—S(O)₂N(alkyl)₂, —S(O)₂N(alkyl)(aryl), —OCF₃, —OH, —OR²⁰,—O-heterocycloalkyl, —O-cycloalkylalkyl, —O-heterocycloalkylalkyl, —NH₂,—NHR²⁰, —N(alkyl)₂, —N(arylalkyl)₂, —N(arylalkyl)-(heteroarylalkyl),—NHC(O)R²⁰, —NHC(O)NH₂, —NHC(O)NH(alkyl), —NHC(O)N(alkyl)(alkyl),—N(alkyl)C(O)NH(alkyl), —N(alkyl)C(O)N(alkyl)(alkyl), —NHS(O)₂R²⁰,—NHS(O)₂NH(alkyl), —NHS(O)₂N(alkyl)(alkyl), —N(alkyl)S(O)₂NH(alkyl) and—N(alkyl)S(O)₂N(alkyl)(alkyl); or two R¹⁸ moieties on adjacent carbonsare optionally linked together to form

R¹⁹ is alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,heterocycloalkylalkyl, arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl, orheterocycloalkenylheteroaryl, R²⁰ is halo substituted aryl, alkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl,arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl,heterocycloalkenylheteroaryl, and wherein each of the each of the alkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl,arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl,heterocycloalkenylheteroaryl, in R, R¹, R², R³, R⁴, R⁵, R⁶, R⁷ R⁸, R⁹,R^(10 , R) ¹¹, R¹², R¹³ and R¹⁴ are independently unsubstituted orsubstituted by 1 to 5 R²¹ groups independently selected from the groupconsisting of alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,heterocycloalkylalkyl, arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl,heterocycloalkenylheteroaryl, halo, —CN, —OR¹⁵, —C(O)R¹⁵, —C(O)OR¹⁵,—C(O)N(R¹⁵)(R¹⁶), —SR¹⁵, —S(O)N(R¹⁵)(R¹⁶), —CH(R¹⁵)(R¹⁶),—S(O)₂N(R¹⁵)(R¹⁶), —C(═NOR¹⁵)R¹⁶, —P(O)(OR¹⁵)(OR¹⁶), —N(R¹⁵)(R¹⁶),-alkyl-N(R¹⁵)(R¹⁶), —N(R¹⁵)C(O)R¹⁶, —CH₂—N(R¹⁵)C(O)R¹⁶,—CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —CH₂—R¹⁵; —CH₂N(R¹⁵)(R¹⁶), —N(R¹⁵)S(O)R¹⁶,—N(R¹⁵)S(O)₂R¹⁶, —CH₂—N(R¹⁵)S(O)₂R¹⁶, —N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷),—N(R¹⁵)S(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷),—CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)OR¹⁶, —CH₂—N(R¹⁵)C(O)OR¹⁶,—S(O)R¹⁵, —N₃, —NO₂and —S(O)₂R¹⁵; and wherein each of the alkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl,arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl, andheterocycloalkenylheteroaryl groups in R²¹ are independentlyunsubstituted or substituted by 1 to 5 R²² groups independently selectedfrom the group consisting of alkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkylalkyl,heteroarylcycloalkylalkyl, arylheterocycloalkylalkyl,heteroarylheterocycloalkylalkyl, cycloalkyl, arylcycloalkyl,heteroarylcycloalkyl, heterocycloalkyl, arylheterocycloalkyl,heteroarylheterocycloalkyl, alkenyl, arylalkenyl, cycloalkenyl,arylcycloalkenyl, heteroarylcycloalkenyl, heterocycloalkenyl,arylheterocycloalkenyl, heteroarylheterocycloalkenyl, alkynyl,arylalkynyl, aryl, cycloalkylaryl, heterocycloalkylaryl,cycloalkenylaryl, heterocycloalkenylaryl, heteroaryl,cycloalkylheteroaryl, heterocycloalkylheteroaryl,cycloalkenylheteroaryl, heterocycloalkenylheteroaryl, halo, —CF₃, —CN,—OR¹⁵, —C(O)R¹⁵, —C(O)OR¹⁵, -alkyl-C(O)OR¹⁵, C(O)N(R¹⁵)(R¹⁶), —SR¹⁵,—S(O)N(R¹⁵)(R¹⁶), —S(O)₂N(R¹⁵)(R¹⁶), —C(═NOR¹⁵)R¹⁶, —P(O)(OR¹⁵)(OR¹⁶),—N(R¹⁵)(R¹⁶), -alkyl-N(R¹⁵)(R¹⁶), —N(R¹⁵)C(O)R¹⁶, —CH₂—N(R¹⁵)C(O)R¹⁶,—N(R¹⁵)S(O)R¹⁶, —N(R¹⁵)S(O)₂R¹⁶, —CH₂—N(R¹⁵)S(O)₂R¹⁶,—N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷), —N(R¹⁵)S(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷),—CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)OR¹⁶, —CH₂—N(R¹⁵)C(O)OR¹⁶, —N₃,—NO₂, —S(O)R¹⁵ and —S(O)₂R¹⁵; or two R²¹ or two R²² moieties on adjacentcarbons are optionally linked together to form

and when R²¹ or R²² are selected from the group consisting of—C(═NOR¹⁵)R¹⁶, —N(R¹⁵)C(O)R¹⁶, —CH₂—N(R¹⁵)C(O)R¹⁶, —N(R¹⁵)S(O)R¹⁶,—N(R¹⁵)S(O)₂R¹⁶, —CH₂—N(R¹⁵)S(O)₂R¹⁶, —N(R¹⁵)S(O)₂N(R^(16 )(R) ¹⁷),—N(R¹⁵)S(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷),—CH₂—N(R¹⁵)C(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)OR¹⁶ and —CH₂—N(R¹⁵)C(O)OR¹⁶, R¹⁵and R¹⁶ together are optionally a C₂ to C₄ chain wherein, one, two orthree ring carbons are optionally replaced by —C(O)— or —N(H)— and R¹⁵and R¹⁶, together with the atoms to which they are attached, form a 5 to7 membered ring, optionally substituted by R²³; R²³ is 1 to 5 groupsindependently selected from the group consisting of alkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl,arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl,heterocycloalkenylheteroaryl, halo, —CN, —OR²⁴, —C(O)R²⁴, —C(O)OR²⁴,—C(O)N(R²⁴)(R²⁵), —SR²⁴, —S(O)N(R²⁴)(R²⁵), —S(O)₂N(R²⁴)(R²⁵),—C(═NOR²⁴)R²⁵, —P(O)(OR²⁴)(OR²⁵), —N(R²⁴)(R²⁵), -alkyl-N(R²⁴)(R²⁵),—N(R²⁴)C(O)R²⁵, —CH₂—N(R²⁴)C(O)R²⁵, —N(R²⁴)S(O)R²⁵, —N(R²⁴)S(O)₂R²⁵,—CH₂—N(R²⁴)S(O)₂R²⁵, —N(R²⁴)S(O)₂N(R²⁵)(R²⁶), —N(R²⁴)S(O)N(R²⁵)(R²⁶),—N(R²⁴)C(O)N(R²⁵)(R²⁶), —CH₂—N(R²⁴)C(O)N(R²⁵)(R²⁶), —N(R²⁴)C(O)OR²⁵,—CH₂—N(R²⁴)C(O)OR²⁵, —S(O)R²⁴ and —S(O)₂R²⁴; and wherein each of thealkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,heterocycloalkylalkyl, arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl andheterocycloalkenylheteroaryl groups in R²³ are independentlyunsubstituted or substituted by 1 to 5 R²⁷ groups independently selectedfrom the group consisting of alkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkylalkyl,heteroarylcycloalkylalkyl, arylheterocycloalkylalkyl,heteroarylheterocycloalkylalkyl, cycloalkyl, arylcycloalkyl,heteroarylcycloalkyl, heterocycloalkyl, arylheterocycloalkyl,heteroarylheterocycloalkyl, alkenyl, arylalkenyl, cycloalkenyl,arylcycloalkenyl, heteroarylcycloalkenyl, heterocycloalkenyl,arylheterocycloalkenyl, heteroarylheterocycloalkenyl, alkynyl,arylalkynyl, aryl, cycloalkylaryl, heterocycloalkylaryl,cycloalkenylaryl, heterocycloalkenylaryl, heteroaryl,cycloalkylheteroaryl, heterocycloalkylheteroaryl,cycloalkenylheteroaryl, heterocycloalkenylheteroaryl, halo, —CF₃, —CN,—OR²⁴, —C(O)R²⁴, —C(O)OR²⁴, alkyl-C(O)OR²⁴, C(O)N(R²⁴)(R²⁵) —SR²⁴,—S(O)N(R²⁴)(R²⁵), —S(O)₂N(R²⁴)(R²⁵), —C(═NOR²⁴)R²⁵, —P(O)(OR²⁴)(OR²⁵),—N(R²⁴)(R²⁵), -alkyl-N(R²⁴)(R²⁵), —N(R²⁴)C(O)R²⁵, —CH₂—N(R²⁴)C(O)R²⁵,—N(R²⁴)S(O)R²⁵, —N(R²⁴)S(O)₂R²⁵, —CH₂—N(R²⁴)S(O)₂R²⁵,—N(R²⁴)S(O)₂N(R²⁵)(R²⁶), —N(R²⁴)S(O)N(R²⁵)(R²⁶), —N(R²⁴)C(O)N(R²⁵)(R²⁶),—CH₂—N(R²⁴)C(O)N(R²⁵)(R²⁶) —N(R²⁴)C(O)OR²⁵, —CH₂—N(R²⁴)C(O)OR²⁵,—S(O)R²⁴ and —S(O)₂R²⁴; R²⁴, R²⁵ and R²⁶ are independently selected fromthe group consisting of H, alkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkylalkyl,heteroarylcycloalkylalkyl, arylheterocycloalkylalkyl,heteroarylheterocycloalkylalkyl, cycloalkyl, arylcycloalkyl,heteroarylcycloalkyl, heterocycloalkyl, arylheterocycloalkyl,heteroarylheterocycloalkyl, alkenyl, arylalkenyl, cycloalkenyl,arylcycloalkenyl, heteroarylcycloalkenyl, heterocycloalkenyl,arylheterocycloalkenyl, heteroarylheterocycloalkenyl, alkynyl,arylalkynyl, aryl, cycloalkylaryl, heterocycloalkylaryl,cycloalkenylaryl, heterocycloalkenylaryl, heteroaryl,cycloalkylheteroaryl, heterocycloalkylheteroaryl,cycloalkenylheteroaryl, heterocycloalkenylheteroaryl, R²⁷-alkyl,R²⁷-arylalkyl, R²⁷-heteroarylalkyl, R²⁷-cycloalkylalkyl,R²⁷-heterocycloalkylalkyl, R²⁷-arylcycloalkylalkyl,R²⁷-heteroarylcycloalkylalkyl, R²⁷-arylheterocycloalkylalkyl,R²⁷-heteroarylheterocycloalkylalkyl, R²⁷-cycloalkyl, R²⁷-arylcycloalkyl,R²⁷-heteroarylcycloalkyl, R²⁷-heterocycloalkyl,R²⁷-arylheterocycloalkyl, R²⁷-heteroarylheterocycloalkyl, R²⁷-alkenyl,R²⁷-arylalkenyl, R²⁷-cycloalkenyl, R²⁷-arylcycloalkenyl,R²⁷-heteroarylcycloalkenyl, R²⁷-heterocycloalkenyl,R²⁷-arylheterocycloalkenyl, R²⁷-heteroarylheterocycloalkenyl,R²⁷-alkynyl, R²⁷-arylalkynyl, R²⁷-aryl, R²⁷-cycloalkylaryl,R²⁷-heterocycloalkylaryl, R²⁷-cycloalkenylaryl,R²⁷-heterocycloalkenylaryl, R²⁷-heteroaryl, R²⁷-cycloalkylheteroaryl,R²⁷-heterocycloalkylheteroaryl, R²⁷-cycloalkenylheteroaryl andR²⁷-heterocycloalkenylheteroaryl; R²⁷ is 1-5 substituents independentlyselected from the group consisting of alkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkylalkyl,heteroarylcycloalkylalkyl, arylheterocycloalkylalkyl,heteroarylheterocycloalkylalkyl, cycloalkyl, arylcycloalkyl,heteroarylcycloalkyl, heterocycloalkyl, arylheterocycloalkyl,heteroarylheterocycloalkyl, alkenyl, arylalkenyl, cycloalkenyl,arylcycloalkenyl, heteroarylcycloalkenyl, heterocycloalkenyl,arylheterocycloalkenyl, heteroarylheterocycloalkenyl, alkynyl,arylalkynyl, aryl, cycloalkylaryl, heterocycloalkylaryl,cycloalkenylaryl, heterocycloalkenylaryl, heteroaryl,cycloalkylheteroaryl, heterocycloalkylheteroaryl,cycloalkenylheteroaryl, heterocycloalkenylheteroaryl, —NO₂, halo, —CF₃,—CN, alkyl-CN, —C(O)R²⁸, —C(O)OH, —C(O)OR²⁸, —C(O)NHR²⁹, —C(O)N(alkyl)₂,—C(O)N(alkyl)(aryl), —C(O)N(alkyl)(heteroaryl), —SR²⁸, —S(O)₂R²⁹,—S(O)NH₂, —S(O)NH(alkyl), —S(O)N(alkyl)(alkyl), —S(O)NH(aryl),—S(O)₂NH₂, —S(O)₂NHR²⁸, —S(O)₂NH(aryl), —S(O)₂NH(heterocycloalkyl),—S(O)₂N(alkyl)₂, —S(O)₂N(alkyl)(aryl), —OH, —OR²⁹, —O-heterocycloalkyl,—O-cycloalkylalkyl, —O-heterocycloalkylalkyl, —NH₂, —NHR²⁹, —N(alkyl)₂,—N(arylalkyl)₂, —N(arylalkyl)(heteroarylalkyl), —NHC(O)R²⁹, —NHC(O)NH₂,—NHC(O)NH(alkyl), —NHC(O)N(alkyl)(alkyl), —N(alkyl)C(O)NH(alkyl),—N(alkyl)C(O)N(alkyl)(alkyl), —NHS(O)₂R²⁹, —NHS(O)₂NH(alkyl),—NHS(O)₂N(alkyl)(alkyl), —N(alkyl)S(O)₂NH(alkyl) and—N(alkyl)S(O)₂N(alkyl)(alkyl); R²⁸ is alkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkylalkyl,heteroarylcycloalkylalkyl, arylheterocycloalkylalkyl,heteroarylheterocycloalkylalkyl, cycloalkyl, arylcycloalkyl,heteroarylcycloalkyl, heterocycloalkyl, arylheterocycloalkyl,heteroarylheterocycloalkyl, alkenyl, arylalkenyl, cycloalkenyl,arylcycloalkenyl, heteroarylcycloalkenyl, heterocycloalkenyl,arylheterocycloalkenyl, heteroarylheterocycloalkenyl, alkynyl,arylalkynyl, aryl, cycloalkylaryl, heterocycloalkylaryl,cycloalkenylaryl, heterocycloalkenylaryl, heteroaryl,cycloalkylheteroaryl, heterocycloalkylheteroaryl, cycloalkenylheteroarylor heterocycloalkenylheteroaryl; R²⁹ is alkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl,arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl orheterocycloalkenylheteroaryl; R³⁰ is independently selected from thegroup consisting of H, alkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkylalkyl,heteroarylcycloalkylalkyl, arylheterocycloalkylalkyl,heteroarylheterocycloalkylalkyl, cycloalkyl, arylcycloalkyl,heteroarylcycloalkyl, heterocycloalkyl, arylheterocycloalkyl,heteroarylheterocycloalkyl, alkenyl, arylalkenyl, cycloalkenyl,arylcycloalkenyl, heteroarylcycloalkenyl, heterocycloalkenyl,arylheterocycloalkenyl, heteroarylheterocycloalkenyl, alkynyl,arylalkynyl, aryl, cycloalkylaryl, heterocycloalkylaryl,cycloalkenylaryl, heterocycloalkenylaryl, heteroaryl,cycloalkylheteroaryl, heterocycloalkylheteroaryl,cycloalkenylheteroaryl, heterocycloalkenylheteroaryl, —OR¹⁵,—N(R¹⁵)(R¹⁶), —N(R¹⁵)C(O)R¹⁶, —N(R¹⁵)S(O)R¹⁶, —N(R¹⁵)S(O)₂R¹⁶,—N(R¹⁵)S(O)₂N(R¹⁶)(R¹⁷), —N(R¹⁵)S(O)N(R¹⁶)(R¹⁷), —N(R¹⁵)C(O)N(R¹⁶)(R¹⁷)and —N(R¹⁵)C(O)OR¹⁶; and R³¹ is independently selected from the groupconsisting of H, alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,heterocycloalkylalkyl, arylcycloalkylalkyl, heteroarylcycloalkylalkyl,arylheterocycloalkylalkyl, heteroarylheterocycloalkylalkyl, cycloalkyl,arylcycloalkyl, heteroarylcycloalkyl, heterocycloalkyl,arylheterocycloalkyl, heteroarylheterocycloalkyl, alkenyl, arylalkenyl,cycloalkenyl, arylcycloalkenyl, heteroarylcycloalkenyl,heterocycloalkenyl, arylheterocycloalkenyl,heteroarylheterocycloalkenyl, alkynyl, arylalkynyl, aryl,cycloalkylaryl, heterocycloalkylaryl, cycloalkenylaryl,heterocycloalkenylaryl, heteroaryl, cycloalkylheteroaryl,heterocycloalkylheteroaryl, cycloalkenylheteroaryl andheterocycloalkenylheteroaryl.
 2. A compound of claim 1 with thefollowing structures:


3. A compound of claim 1 wherein —R¹—R²— is -alkylene-N(R⁵)—C(O)—,-alkylene-C(O)— or -alkylene-O-alkylene-.
 4. A compound of claim 1wherein R numbers 1 to 3 and R is alk-yl, —C(O)R³⁰, halo or —S(O)₂R³¹.5. A compound of claim 4 wherein R³⁰ or R³¹ is alkyl.
 6. A compound ofclaim 1 wherein W is —C(O)—; U is a bond; —R¹—R²— is -alkylene-O—C(O)—;R is halo; R³ is alkyl; R⁴ is aryl-R²¹; R²¹ is aryl-R²²; and R²² is —CN.7. A compound of claim 1 wherein W is —C(O)—; U is a bond; —R¹—R²— is—CH₂—C(R)₂—O—C(O)—; R is F; R³is —CH₃; and R⁴ is


8. A compound of claim 1 wherein W is —C(O)—; U is a bond; —R¹—R²— is—CH₂—CH₂—N(R⁵)—C(O)—; R is —C(O)R³⁰; R³ is alkyl; R⁴ is aryl-R²¹; R²¹ isaryl-R²²; R²² is —CN; and R³⁰ is alkyl.
 9. A compound of claim 1 whereinW is —C(O)—; U is a bond; —R¹—R²— is —CH₂—CH₂—N(R⁵)—C(O)—; R is—C(O)R³⁰; R³ is —CH₃; R⁴ is

and R³⁰ is —CH₃.
 10. A compound of claim 1 wherein W is —C(O)—; U is abond; —R¹—R²— is —CH₂—CH₂—N(R⁵)—C(O)—; R is —S(O)₂R³¹; R³is alkyl; R⁴isaryl-R²¹; R²¹ is aryl-R²²; R²² is —CN; and R³¹ is alkyl.
 11. A compoundof claim 1 wherein W is —C(O)—; U is a bond; —R¹—R²— is—CH₂—CH₂—N(R⁵)—C(O)—; R is —S(O)₂R³¹; R³is —CH₃; R⁴ is

and R³¹ is —CH₃.
 12. A compound of claim 1 wherein W is —C(O)—; U is abond; —R¹—R²— is —CH₂—CH₂—O—C(R)₂—; R is alkyl; R³is alkyl; R⁴ isaryl-R²¹; R²¹ is aryl-R²²; and R²² is —CN.
 13. A compound of claim 1wherein W is —C(O)—; U is a bond; —R¹—R²— is —CH₂—CH₂—O—C(R)₂—; R ismethyl; R³ is —CH³; and R⁴ is


14. A compound of claim 1 with the following structures:


15. A compound of claim 1 wherein —R¹—R²— is -alkylene-, or-alkylene-C(O)—.
 16. A compound of claim 14 wherein R is H.
 17. Acompound of claim 1 wherein W is —C(O)—; U is a —C(R⁶)(R⁷); —R¹—R²— is-alkylene-C(O)—; R is H; R³ is H; R⁴ is H; R⁶ is alkyl; and R⁷ isheteroaryl.
 18. A compound of claim 1 wherein W is —C(O)—; U is a—C(R⁶)(R⁷)—; —R¹—R²— is —CH₂—C(O)—; R is H; R³ is H; R⁴ is H; R⁶ is—CH₃; and R⁷ is


19. A compound of claim 1 wherein W is —C(O)—; U is a —C(R⁶)(R⁷)—;—R¹—R²— is -alkylene-; R is H; R³ is H; R⁴ is H; R⁶ is alkyl; and R⁷ isheteroaryl.
 20. A compound of claim 1 wherein W is —C(O)—; U is a—C(R⁶)(R⁷)—; —R¹—R²— is —CH₂—CH₂—CH₂—CH₂—; R is H; R³ is H; R⁴ is H; R⁶is —CH₃; and R⁷ is


21. A compound of claim 1 wherein W is —C(O)—; U is a bond; —R¹—R²— is-alkylene-; R is H; R³ is aryl; and R⁴ is aryl.
 22. A compound of claim1 wherein W is —C(O)—; U is a bond; —R¹—R²— is —CH₂—CH₂—CH₂—; R is H; R³is

and R⁴ is


23. A compound selected from the group consisting of:


24. A pharmaceutical composition comprising an effective amount of acompound of claim 1 and a pharmaceutically effective carrier.
 25. Apharmaceutical composition comprising an effective amount of a compoundof claim 23 and a pharmaceutically effective carrier.
 26. A method ofinhibiting aspartyl protease comprising administering to a patient inneed of such treatment an effective amount of a compound of claim
 1. 27.A method of inhibiting aspartyl protease comprising administering to apatient in need of such treatment an effective amount of a compound ofclaim
 23. 28. A method of treating cardiovascular diseases, cognitiveand neurodegenerative diseases, and the methods of inhibiting of HumanImmunodeficiency Virus, plasmepins, cathepsin D and protozoal enzymescomprising administering to a patient in need of such treatment aneffective amount of a compound of claim
 1. 29. The method of claim 28wherein a cognitive or neurodegenerative disease is treated.
 30. Themethod of claim 29 wherein Alzheimer's Disease is treated.
 31. A methodof treating cardiovascular diseases, cognitive and neurodegenerativediseases, and the methods of inhibiting of Human Immunodeficiency Virus,plasmepins, cathepsin D and protozoal enzymes comprising administeringto a patient in need of such treatment an effective amount of a compoundof claim
 23. 32. The method of claim 31 wherein a cognitive orneurodegenerative disease is treated.
 33. The method of claim 32 whereinAlzheimer's Disease is treated.
 34. A pharmaceutical compositioncomprising an effective amount of a compound of claim 1, and aneffective amount of a cholinesterase inhibitor or a muscarinic m₁agonist or m₂ antagonist in a pharmaceutically effective carrier.
 35. Apharmaceutical composition comprising an effective amount of a compoundof claim 23, and an effective amount of a cholinesterase inhibitor or amuscarinic m₁ agonist or m₂ antagonist in a pharmaceutically effectivecarrier.
 36. A method of treating a cognitive or neurodegenerativedisease comprising administering to a patient in need of such treatmentan effective amount of a compound of claim 1 in combination with aneffective amount of a cholinesterase inhibitor.
 37. The method of claim36 wherein Alzheimer's Disease is treated.
 38. A method of treating acognitive or neurodegenerative disease comprising administering to apatient in need of such treatment an effective amount of a compound ofclaim 23 in combination with an effective amount of a cholinesteraseinhibitor.
 39. The method of claim 38 wherein Alzheimer's Disease istreated.
 40. A method of treating a cognitive or neurodegenerativedisease comprising administering to a patient in need of such treatmentan effective amount of a compound of claim 1 in combination with aneffective amount of a gamma secretase inhibitor, an HMG-CoA reductaseinhibitor or non-steroidal anti-inflammatory agent.
 41. The method ofclaim 40 wherein said HMG-CoA reductase inhibitor is atorvastatin,lovastatin, simvastatin, pravastatin, fluvastatin or rosuvastatin. 42.The method of claim 41 wherein Alzheimer's Disease is treated.
 43. Themethod of claim 40 wherein said non-steroidal anti-inflammatory agent isibuprofen, relafen or naproxen.
 44. The method of claim 43 whereinAlzheimer's Disease is treated.
 45. A method of treating a cognitive orneurodegenerative disease comprising administering to a patient in needof such treatment an effective amount of a compound of claim 23 incombination with an effective amount of a gamma secretase inhibitor, anHMG-CoA reductase inhibitor or non-steroidal anti-inflammatory agent.46. The method of claim 45 wherein said HMG-CoA reductase inhibitor isatorvastatin, lovastatin, simvastatin, pravastatin, fluvastatin orrosuvastatin.
 47. The method of claim 46 wherein Alzheimer's Disease istreated.
 48. The method of claim 45 wherein said non-steroidalanti-inflammatory agent is ibuprofen, relafen or naproxen.
 49. Themethod of claim 48 wherein Alzheimer's Disease is treated.
 50. Apharmaceutical composition comprising an effective amount of a compoundof claim 1, and an effective amount of a gamma secretase inhibitor; anHMG-CoA reductase inhibitor or a non-steroidal anti-inflammatory agent.51. A pharmaceutical composition comprising an effective amount of acompound of claim 23, and an effective amount of a gamma secretaseinhibitor; an HMG-CoA reductase inhibitor or a non-steroidalanti-inflammatory agent.
 52. A method of treating a cognitive orneurodegenerative disease comprising administering to a patient in needof such treatment an effective amount of at least one compound of claim1 in combination with an effective amount of one or more compoundsselected from the group consisting of a cholinesterase inhibitor,muscarinic m₁ agonist or m₂ antagonist, gamma secretase inhibitor, anHMG-CoA reductase inhibitor and non-steroidal anti-inflammatory agent.53. A method of treating a cognitive or neurodegenerative diseasecomprising administering to a patient in need of such treatment aneffective amount of at least one compound of claim 23 in combinationwith an effective amount of one or more compounds selected from thegroup consisting of a cholinesterase inhibitor, muscarinic m₁ agonist orm₂ antagonist, gamma secretase inhibitor, an HMG-CoA reductase inhibitorand non-steroidal anti-inflammatory agent.